Modular synthesis of aminoglycosides

ABSTRACT

The present disclosure relates to novel methods for preparing antibacterial aminoglycoside compounds and the compounds used in such preparations.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/652,169, filed Apr. 3, 2018, the content of which is incorporatedherein by reference in its entirety.

FIELD OF THE DISCLOSURE

The present disclosure relates to novel synthetic methods for preparingaminoglycoside compounds, as well as to related intermediates.

BACKGROUND OF THE DISCLOSURE

Chemical synthesis, biosynthesis, and semi-synthesis on natural productsare efficient means to procure amounts of oligosaccharide materials forassessment of therapeutic benefit in a wide variety of diseases [Anish,C.; Schumann, B.; Pereira, C. L.; Seeberger, P. H. Chem. Biol. 2014 ,21, 38-50. ].

Highly functionalized aminoglycoside di-, tri-, and tetra-saccharideshave found utility in anti-bacterial therapeutics and are denselyfunctionalized molecules on a carbohydrate backbone [Arya, D. P.Aminoglycoside Antibiotics: From Chemical Biology to Drug Discovery;Wiley: Hoboken, N.J., 2007]. These molecules are often prepared fromnatural and unnatural products formed from biosynthesis in combinationwith chemical synthesis and require judicious use of protecting groupsand careful analysis of stereochemistry at newly created functionalgroups and/or glycosyl positions [Garneau-Tsodikova, S.; Chandrika, N.T.; Chemical Society Reviews (2018), 47(4), 1189-1249].

Given the complexity of performing synthetic chemistry on such denselyfunctionalized and protected molecules, previous efforts in the fieldhave led to modifications on the periphery [Cao, H.; Hwang, J.; Chen,X.; Opportunity, Challenge and Scope of Natural Products in MedicinalChemistry (2011), 411-431] with only a few examples of modifications tothe backbone [highlighted in bold, shown below] of the complexcarbohydrate structure:

[Silva, J. G.; Carvalho, I.; Current Medicinal Chemistry (2007), 14(10),1101-1119] and multiple reports on the lack of access to said molecules[Qin, C.; Schuumann, B.; Zou, X.; Periera, C. L.; Tian, G.; Hu, J.;Seeberger, P. H.; Yin, J.; J. Am. Chem. Soc. 2018, 140, 3120-3127 andreferences therein] which may represent novel therapeutics.

SUMMARY OF THE DISCLOSURE

In brief, the present disclosure relates to novel synthetic methods forpreparing antibacterial aminoglycoside compounds and novelintermediates.

The present disclosure provides a process for preparing a compound offormula A-5,

wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl,—SR^(22, —SO) ₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H, alkyl,amino protecting group, or hydroxyl protecting group; wherein the C₁-C₆alkyl or alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of aryl, halogen, —OR³⁰,—NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X¹ is F, —Cl, —Br, or I;

LVG¹ is a leaving group;

N^(1a) is —NHPg^(1a), —N(Pg^(1a))₂, or N₃, wherein each Pg^(1a) isindependently an amino protecting group;

m is zero, 1, or 2;

n is zero, 1, or 2; and,

-   -   wherein m+n is 1, 2 or 3;

or a salt, solvate, enantiomer, or diastereomer thereof, comprising:

(a) contacting a compound of formula A-1:

or a salt, solvate, enantiomer, or diastereomer thereof, with a chiralauxiliary reagent to yield a compound of formula A-2:

or a salt, solvate, enantiomer, or diastereomer thereof,

wherein Xc is a chiral auxiliary group;

(b) contacting the compound of formula A-2 with a Grignard ororganolithium reagent to yield a compound of formula A-3:

or a salt, solvate, enantiomer, or diastereomer thereof,

(c) contacting the compound of formula A-3 with a halogen reagent inpresence of a nucleophile reagent (Nuc-1) to yield a compound of formulaA-4:

or a salt, solvate, enantiomer, or diastereomer thereof; wherein

X¹ is —F, —Cl, —Br, or —I;

Nuc-1 is LVG¹-M, wherein M is H, a metal cation, a non-metal cation, ora lone pair of electrons;

LVG¹ is a leaving group;

(d) exchanging the chiral auxiliary group for an amino protecting groupin the compound of formula A-4 by reaction with an amino protectinggroup reagent to yield the compound of formula A-5:

or a salt, solvate, enantiomer, or diastereomer thereof,

wherein N^(1a) is —NHPg^(1a), —N(Pg^(1a))₂, or N₃, wherein Pg^(1a) is anamino protecting group.

The present disclosure provides a process for preparing a compound offormula A-5a,

wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), and R^(3a) are independently selected from the groupconsisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, and C₁-C₆alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H, alkyl, aminoprotecting group, or hydroxyl protecting group; wherein the C₁-C₆ alkylor alkyl is unsubstituted or substituted with one or more substituentsselected from the group consisting of aryl, halogen, —OR³⁰, —NR³¹R³²,—SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3b) is H;

N^(1b) is —NHPg^(1b), —N(Pg^(1b))₂, or N₃, wherein each Pg^(1a) isindependently an amino protecting group;

X² is —F, —Cl, —Br, or —I;

LVG² is a leaving group.

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

or a salt, solvate, enantiomer, or diastereomer thereof, comprising:

(a) converting —OH in the compound of formula A-7

or a salt, solvate, enantiomer, or diastereomer thereof, to R^(3a) toyield a compound of formula A-8:

or a salt, solvate, enantiomer, or diastereomer thereof, wherein

(b) contacting the compound of formula A-8 with a halogen reagent inpresence of a nucleophile reagent (Nuc-2) to yield a compound of formulaA-5a:

or a salt, solvate, enantiomer, or diastereomer thereof;

wherein

X² is F, —Cl, —Br, or —I;

Nuc-2 is LVG²-M, wherein M is H, a metal cation, a non-metal cation, ora lone pair of electrons;

LVG² is a leaving group.

The present disclosure provides a process for preparing a compound offormula B-6′:

wherein

R^(4aa) and R^(4bb) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H, alkyl, —CONH₂, or—COCH₃; wherein the alkyl is unsubstituted or substituted with one ormore substituents selected from the group consisting of —CONH₂, —OH,—NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen, andsubstituted heteroaryl;

R^(5aa) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —OC(O)CH₃, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2o); wherein Pg^(2o) is a hydroxyl protecting group;

R⁸ is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(49z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(8b) is H or C₁-C₃alkyl;

N^(1c) is —NHPg^(1c) or N₃, wherein Pg^(1c) is an amino protecting group

Pg^(2b) is a hydroxyl protecting group;

o is zero, 1, or 2;

p is zero, 1, or 2;

wherein o+p is 1, 2 or 3;

or a salt, solvate, enantiomer, or diastereomer thereof, comprising:

(a) contacting a compound of formula B-1′:

or a salt, solvate, enantiomer, or diastereomer thereof, with an aminoprotecting group reagent and a hydroxyl protecting group reagent toyield a compound of formula B-2′:

or a salt, solvate, enantiomer, or diastereomer thereof;

wherein Pg^(2a) is a hydroxyl protecting group;

(b) converting the amino group of the compound of formula B-2′ at C1 toan azide group;

(c) converting the azide group of the compound of formula B-2′ at C1 toa hydroxyl group;

(d) oxidizing the hydroxyl group of the compound of formula B-2′ at C1to an oxo group to yield a compound of formula B-3′:

or a salt, solvate, enantiomer, or diastereomer thereof;

(e) converting the oxo group of the compound of formula B-3′ to an iminogroup and contacting with an amino reactive reagent to yield a compoundof formula B-4′:

or a salt, solvate, enantiomer, or diastereomer thereof;

(f) contacting the compound of formula B-4′ with a Grignard ororganolithium reagent to yield a compound of formula B-5′:

or a salt, solvate, enantiomer, or diastereomer thereof,

(g) forming a hydroxyl group by selective removal of the Pg^(2a)protecting group of the compound of formula B-5′ to yield the compoundof formula B-6′:

or a salt, solvate, enantiomer, or diastereomer thereof.

The present disclosure provides a process for preparing a compound offormula B-11′:

wherein

R^(4aa) and R^(4bb) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H, alkyl, —CONH₂, or—COCH₃; wherein the alkyl is unsubstituted or substituted with one ormore substituents selected from the group consisting of —CONH₂, —OH,—NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen, andsubstituted heteroaryl;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2o); wherein Pg^(2o) is a hydroxyl protecting group;

N^(1s) is N₃ or —NR⁸R^(8b);

R⁸ is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(8b) is H or C₁-C₃alkyl;

N^(1d) is —NHPg^(1d) or N₃, wherein Pg^(1d) is an amino protectinggroup;

Pg^(2d) is a hydroxyl protecting group;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

or a salt, solvate, enantiomer, or diastereomer thereof, comprising:

(a) contacting a compound of formula B-8′:

or a salt, solvate, enantiomer, or diastereomer thereof, wherein N^(1dx)is —NH₂, —NHPg^(1d) or N₃, wherein Pg^(1d) is an amino protecting group,

with a first selective hydroxyl protecting group reagent; a secondselective hydroxyl protecting group reagent; an amino protecting groupreagent, if N^(1dx) is —NH₂; and an amino reactive reagent, if N^(1s) is—NR⁸R^(8b), to yield a compound of formula B-9′:

or a salt, solvate, enantiomer, or diastereomer thereof; wherein Pg^(2c)is a hydroxyl protecting group;

(b) contacting the compound of formula B-9′ with a electrophilic reagentor oxidizing the alcohol at C6 to an oxo group and contacting the oxogroup with a nucleophilic reagent to yield a compound of formula B-10′:

or a salt, solvate, enantiomer, or diastereomer thereof,

c) forming a hydroxyl group by selective removal of the Pg^(2c)protecting group of the compound of formula B-10′ to yield the compoundof formula B-11′:

or a salt, solvate, enantiomer, or diastereomer thereof.

The present disclosure provides a process for preparing a compound offormula AB-1′,

wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁵, and R²⁶ is independently H or alkyl, whereinthe alkyl is unsubstituted or substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,NR¹⁴R¹⁵ and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H, alkyl,amino protecting group, or hydroxyl protecting group; wherein the C₁-C₆alkyl or alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of aryl, halogen, —OR³⁰,—NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(1a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(4aa) and R^(4bb) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H, alkyl, —CONH₂, or—COCH₃; wherein the alkyl is unsubstituted or substituted with one ormore substituents selected from the group consisting of —CONH₂, —OH,—NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen, andsubstituted heteroaryl;

R^(5aa) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —OC(O)CH₃, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2m); wherein Pg^(2m) is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(49z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(8b) is H or C₁-C₃alkyl;

N^(1e) is —OH, protected hydroxyl group, —NHPg^(1e) or N₃, whereinPg^(1e) is an amino protecting group;

N^(1f) is —NHPg^(1f) or N₃, wherein Pg^(1f) is an amino protectinggroup;

Pg^(2e) is a hydroxyl protecting group;

X⁷ is H, —NH₂, —N₃, protected amino group, —OH, protected hydroxylgroup, or halogen;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

or a salt, solvate, enantiomer, or diastereomer thereof, comprising:

(a) contacting a compound of formula A-9′:

wherein LVG³ is a leaving group,

with a compound of formula B-12:

to yield the compound of formula (AB-1′).

The present disclosure provides a process for preparing a compound offormula ABC-1′,

wherein the method comprises preparing a compound of formula AB-1,further comprising:

(b) selectively deprotecting the compound of formula AB-1′ by removingthe Pg^(2e) moiety to yield a compound of formula AB-3:

or a salt, solvate, enantiomer, or diastereomer thereof;

(c) contacting the compound of formula AB-3′ with a compound of formulaC-1,

or a salt, solvate, enantiomer, or diastereomer thereof, wherein

R^(7a), R^(7b), and R^(7c) are, independently, H, NH₂, OH, —OR⁷¹ or—OPg^(2r);

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen,and substituted heteroaryl;

wherein Pg^(2r) is a hydroxyl protecting group;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

Pg^(2f) is a hydroxyl protecting group;

LVG⁴ is a leaving group;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3;

to yield a compound of formula ABC-1′, or a salt, solvate, enantiomer,or diastereomer thereof.

The present disclosure provides a process for preparing a compound offormula ABCD-1′,

wherein the method comprises preparing a compound of formula AB-1′,further comprising:

(b) selectively deprotecting the compound of formula AB-1′ by removingthe Pg^(2e) moiety to yield a compound of formula AB-3′:

or a salt, solvate, enantiomer, or diastereomer thereof;

(c) contacting the compound of formula AB-3′ with a compound of formulaCD-1,

or a salt, solvate, enantiomer, or diastereomer thereof, wherein

R^(7a), R^(7b), and R^(7c) are, independently, H, NH₂, OH, —OR⁷¹ or—OPg^(2r);

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen,and substituted heteroaryl;

wherein Pg^(2r) is a hydroxyl protecting group;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

LVG⁵ is a leaving group;

N^(1g) is —NHPg^(1g) or N₃, wherein Pg^(1g) is an amino protectinggroup;

N^(1h) is —NHPg^(1h) or N₃, wherein Pg^(1h) is an amino protectinggroup;

Pg^(2g) is a hydroxyl protecting group;

Pg^(2h) is a hydroxyl protecting group;

q is zero, 1, or 2;

r is zero, 1, or 2;

wherein q+r is 1, 2 or 3;

to yield a compound of formula ABCD-1, or a salt, solvate, enantiomer,or diastereomer thereof.

The present disclosure provides a process for preparing a compound offormula B-6:

wherein

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl; wherein thealkyl is unsubstituted or substituted with one or more substituentsselected from the group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl,substituted aryl, heteroaryl, halogen, and substituted heteroaryl;

R⁵ is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl is unsubstitutedor substituted with one or more substituents selected from the groupconsisting of —OH, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2o), wherein Pg^(2o) is a hydroxyl protecting group;

R⁸ is H, C₁-C₆ alkyl, an amino protecting group, or

-   -   wherein    -   Q¹ is NH, O, or S;    -   z is an integer from 0 to 4,    -   R^(35z) is H or C₁-C₃ alkyl;    -   each R^(36z) and R^(37z) is independently selected from the        group consisting of H, alkyl, halogen, and —OH, and    -   R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z)        and R^(40z) are independently H or

C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

N^(1c) is —NHPg^(1c) or N₃, wherein Pg^(1c) is an amino protectinggroup;

Pg^(2b) is a hydroxyl protecting group;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

or a salt, solvate, enantiomer, or diastereomer thereof, comprising:

(a) contacting a compound of formula B-1:

or a salt, solvate, enantiomer, or diastereomer thereof, with an aminoprotecting group reagent and a hydroxyl protecting group reagent toyield a compound of formula B-2:

or a salt, solvate, enantiomer, or diastereomer thereof;

wherein Pg^(2a) is a hydroxyl protecting group;

(b) converting the amino group of the compound of formula B-2 at C1 toan azide group;

(c) converting the azide group of the compound of formula B-2 at C1 to ahydroxyl group;

(d) oxidizing the hydroxyl group of the compound of formula B-2 at C1 toan oxo group to yield a compound of formula B-3:

or a salt, solvate, enantiomer, or diastereomer thereof;

(e) converting the oxo group of the compound of formula B-3 to an iminogroup and contacting with an amino reactive reagent to yield a compoundof formula B-4:

or a salt, solvate, enantiomer, or diastereomer thereof;

(f) contacting the compound of formula B-4 with a Grignard ororganolithium reagent to yield a compound of formula B-5:

or a salt, solvate, enantiomer, or diastereomer thereof,

(g) forming a hydroxyl group by selective removal of the Pg^(2a)protecting group of the compound of formula B-6 to yield the compound offormula B-7:

or a salt, solvate, enantiomer, or diastereomer thereof.

The present disclosure provides a process for preparing a compound offormula B-11:

wherein

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl; wherein thealkyl is unsubstituted or substituted with one or more substituentsselected from the group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl,substituted aryl, heteroaryl, halogen, and substituted heteroaryl;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2o); wherein Pg^(2o) is a hydroxyl protecting group;

R⁸ is H, C₁-C₆ alkyl, an amino protecting group, or

-   -   wherein    -   Q¹ is NH, O, or S;    -   z is an integer from 0 to 4,    -   R^(35z) is H or C₁-C₃ alkyl;    -   each R^(36z) and R^(37z) is independently selected from the        group consisting of H, alkyl, halogen, and —OH, and    -   R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z)        and R^(40z) are independently H or

C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

N^(1d) is —NHPg^(1d) or H₃, wherein Pg^(1d) is an amino protectinggroup;

Pg^(2d) is a hydroxyl protecting group;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

or a salt, solvate, enantiomer, or diastereomer thereof, comprising:

(a) contacting a compound of formula B-8:

or a salt, solvate, enantiomer, or diastereomer thereof, with an aminoprotecting group reagent and a first selective hydroxyl protecting groupreagent and a second selective hydroxyl protecting group reagent and anamino reactive reagent to yield a compound of formula B-9:

or a salt, solvate, enantiomer, or diastereomer thereof; wherein Pg^(2c)is a hydroxyl protecting group;

(b) contacting the compound of formula B-9 with a electrophilic reagentto yield a compound of formula B-10:

or a salt, solvate, enantiomer, or diastereomer thereof,

c) forming a hydroxyl group by selective removal of the Pg^(2c)protecting group of the compound of formula B-10 to yield the compoundof formula B-11:

or a salt, solvate, enantiomer, or diastereomer thereof.

The present disclosure provides a process for preparing a compound offormula AB-1,

wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵ and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵,and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, and C₁-C₆alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl;

wherein the alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, halogen, and substitutedheteroaryl;

R^(5a) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2m); wherein Pg^(2m) is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

-   -   wherein    -   Q¹ is NH, O, or S;    -   z is an integer from 0 to 4,    -   R^(35z) is H or C₁-C₃ alkyl;    -   each R^(36z) and R^(37z) is independently selected from the        group consisting of H, alkyl, halogen, and OH, and    -   R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z)        and R^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

N^(1e) is —NHPg^(1e) or N₃, wherein Pg^(1e) is an amino protectinggroup;

N^(1f) is —NHPg^(1f) or N₃, wherein Pg^(1f) is an amino protectinggroup;

Pg^(2e) is a hydroxyl protecting group;

X is —NH₂, —N₃, protected amino group, —OH, or protected hydroxyl group;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3;

or a salt, solvate, enantiomer, or diastereomer thereof, comprising:

(a) contacting a compound of formula A-9:

wherein LVG³ is a leaving group,

with a compound of formula B-12:

to yield the compound of formula (AB-1).

The present disclosure provides a process for preparing a compound offormula ABC-1,

wherein the method comprises preparing a compound of formula AB-1,further comprising:

(b) selectively deprotecting the compound of formula AB-1 by removingthe Pg^(2e) moiety to yield a compound of formula AB-3:

or a salt, solvate, enantiomer, or diastereomer thereof;

(c) contacting the compound of formula AB-3 with a compound of formulaC-1,

or a salt, solvate, enantiomer, or diastereomer thereof, wherein

R^(7a), R^(7b), and R^(7c) are, independently, H, NH₂, OH, —OR⁷¹ or—OPg^(2r);

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen,and substituted heteroaryl;

wherein Pg^(2r) is a hydroxyl protecting group;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

Pg^(2f) is a hydroxyl protecting group;

LVG⁴ is a leaving group;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3;

to yield a compound of formula ABC-1, or a salt, solvate, enantiomer, ordiastereomer thereof.

The present disclosure provides a process for preparing a compound offormula ABCD-1,

wherein the method comprises preparing a compound of formula AB-1,further comprising:

(b) selectively deprotecting the compound of formula AB-1 by removingthe Pg^(2e) moiety to yield a compound of formula AB-3:

or a salt, solvate, enantiomer, or diastereomer thereof;

(c) contacting the compound of formula AB-3 with a compound of formulaCD-1,

or a salt, solvate, enantiomer, or diastereomer thereof, wherein

R^(7a), R^(7b), and R^(7c) are, independently, H, NH₂, OH, —OR⁷¹ or—OPg^(2r);

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen,and substituted heteroaryl;

wherein Pg^(2r) is a hydroxyl protecting group;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

LVG⁵ is a leaving group;

N^(1g) is —NHPg^(1g) or N₃, wherein Pg^(1g) is an amino protectinggroup;

N^(1h) is —NHPg^(1h)or N₃, wherein Pg^(1h) is an amino protecting group;

Pg^(2g) is a hydroxyl protecting group;

Pg^(2h) is a hydroxyl protecting group;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3;

to yield a compound of formula ABCD-1, or a salt, solvate, enantiomer,or diastereomer thereof.

The present disclosure provides a compound of formula A-10′:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵ and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H, alkyl,amino protecting group, or hydroxyl protecting group; wherein the C₁-C₆alkyl or alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of aryl, halogen, —OR³⁰,—NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X³ is selected from the group consisting of H, NH₂, N₃, protected aminogroup, OH, —OPg^(2i), and halogen; wherein Pg^(2i) is a hydroxylprotecting group;

LVG⁶ is a leaving group;

N^(1i) is —OH, protected hydroxyl group, —NHPg^(1i), N(Pg^(1i))₂, —NH₂,or N₃, wherein each Pg^(1i) is independently an amino protecting group;

m is zero, 1, or 2;

n is zero, 1, or 2;

wherein m+n is 1, 2 or 3.

The present disclosure provides a compound of formula B-13′:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(4aa) and R^(4bb) are, independently H, —OH, —OR⁴⁰ , —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H, alkyl, —CONH₂, or—COCH₃; wherein the alkyl is unsubstituted or substituted with one ormore substituents selected from the group consisting of —CONH₂, —OH,—NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen, andsubstituted heteroaryl;

R^(5aa) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —OC(O)CH₃, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j); wherein Pg^(2j) is a hydroxyl protecting group;

N^(1s) is N₃ or —NR^(8a)R^(8b);

R⁸a is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(49z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(8b) is H or C₁-C₃alkyl;

R¹¹ is H, alkyl, —COCH₃, or a hydroxyl protecting group;

N^(1j) is —NHPg^(1j), —NH₂, or N₃, wherein Pg^(1j) is an aminoprotecting group;

Pg^(2s) is H or hydroxyl protecting group;

o is zero, 1, or 2;

p is zero, 1, or 2;

wherein o+p is 1, 2 or 3.

The present disclosure provides a compound of formula AB-4′:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H, alkyl,amino protecting group, or hydroxyl protecting group; wherein the C₁-C₆alkyl or alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of aryl, halogen, —OR³⁰,—NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X⁴ is selected from the group consisting of H, NH₂, N₃, protected aminogroup, OH, —OPg^(2k), and halogen; wherein Pg^(2k) is a hydroxylprotecting group;

R^(4aa) and R^(4bb) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H, alkyl, —CONH₂, or—COCH₃; wherein the alkyl is unsubstituted or substituted with one ormore substituents selected from the group consisting of —CONH₂, —OH,—NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen, andsubstituted heteroaryl;

R^(5aa) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —OC(O)CH₃, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j); wherein Pg^(2j) is a hydroxyl protecting group;

N^(1s) is N₃ or —NR^(8a) R^(8b);

R⁸a is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(49z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(8b) is H or C₁-C₃alkyl;

R¹¹ is H, alkyl, —COCH₃, or a hydroxyl protecting group;

N^(1n) is —OH, protected hydroxyl group, —NHPg^(1m), N(Pg^(1m))₂, —NH₂,or N₃, wherein each Pg^(1m) is independently an amino protecting group;

N^(1n) is —NHPg^(1n), —NH₂, or N₃, wherein Pg^(1n) is an aminoprotecting group;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

wherein o+p is 1, 2 or 3.

The present disclosure provides a compound of formula ABC-3′:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹²R¹³, R¹⁴, R¹⁵ and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R₂₃, —NR₂₄R²⁵, and OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵ and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R^(i5),and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H, alkyl,amino protecting group, or hydroxyl protecting group; wherein the C₁-C₆alkyl or alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of aryl, halogen, —OR³⁰,—NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴ _(R) ¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X⁵ is selected from the group consisting of H, NH₂, N₃, protected aminogroup, OH, —OPg²¹, and halogen; wherein Pg²¹ is a hydroxyl protectinggroup;

R^(4aa) and R^(4bb) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H, alkyl, —CONH₂, or—COCH₃; wherein the alkyl is unsubstituted or substituted with one ormore substituents selected from the group consisting of —CONH₂, —OH,—NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen, andsubstituted heteroaryl;

R^(5aa) is H, —CN, CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —OC(O)CH₃, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j);

wherein Pg^(2j) is a hydroxyl protecting group;

R^(7a), R^(7b), and R^(7c) are, independently, H, OH, —OR⁷¹ or —OPg²;

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl;

wherein Pg² is a hydroxyl protecting group;

N^(1s) is N₃ or —NR^(8a)R^(8b);

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(49z), wherein R^(39z) andR^(49z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(8b) is H or C₁-C₃alkyl;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

N¹⁰ is —OH, protected hydroxyl group, —NHPg^(1o), N(pg^(1o))₂, —NH₂, orN₃, wherein each Pg^(1o) is independently an amino protecting group;

N^(1p) is —NHPg^(1p), —NH₂, or N₃, wherein Pg^(1p) is an aminoprotecting group;

Pg^(2f) is a hydroxyl protecting group or H;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2;

wherein q+r is 1, 2 or 3.

The present disclosure provides a compound of formula ABCD-3′:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, NR²⁴R²⁵, and OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H, alkyl,amino protecting group, or hydroxyl protecting group; wherein the C₁-C₆alkyl or alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of aryl, halogen, —OR³⁰,—NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X⁶ is selected from the group consisting of H, NH₂, N₃, protected aminogroup, OH, —OPg^(2m), and halogen; wherein Pg^(2m) is a hydroxylprotecting group;

R^(4aa) and R^(4bb) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H, alkyl, —CONH₂, or—COCH₃; wherein the alkyl is unsubstituted or substituted with one ormore substituents selected from the group consisting of —CONH₂, —OH,—NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen, andsubstituted heteroaryl;

R^(5aa) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —OC(O)CH₃, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j); wherein Pg^(2j) is a hydroxyl protecting group;

R^(7a), R^(7b), and R^(7c) are, independently, H, OH, —OR⁷¹ or —OPg²;

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl;

wherein Pg² is a hydroxyl protecting group;

N^(1s) is N₃ or —NR^(8a)R^(8b);

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(8b) is H or C₁-C₃alkyl;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

N^(1q) is —OH, protected hydroxyl group, —NHPg^(1q), N(Pg^(1q))₂, —NH₂,or N₃, wherein each Pg^(1i) is independently an amino protecting group;

N^(1r) is —NHPg^(1r) or N₃, wherein Pg^(1r) is an amino protectinggroup;

N^(1g) is —NHPg^(1g) or N₃, wherein Pg^(1g) is an amino protectinggroup;

N^(1h) is —NHPg^(1h) or N₃, wherein Pg^(1h) is an amino protectinggroup;

Pg^(2g) is a hydroxyl protecting group;

Pg^(2h) is a hydroxyl protecting group;

wherein at least one of N^(1q), N^(1r), N^(1g), N^(1h) is not NH₂ orwherein at least one of PG^(2g) or Pg^(2h) is not H or wherein X⁶ is not—OH or —NH₂;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2;

wherein q+r is 1, 2 or 3.

The present disclosure provides a compound of formula A-10:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X³ is selected from the group consisting of H, NH₂, N₃, protected aminogroup, OH, —OPg^(2i), and halogen; wherein Pg^(2i) is a hydroxylprotecting group;

LVG⁶ is a leaving group;

N^(1i) is —NHPg^(1i)—NH₂, or N₃, wherein Pg^(1i) is an amino protectinggroup;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3.

The present disclosure provides a compound of formula B-13:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl; wherein thealkyl is unsubstituted or substituted with one or more substituentsselected from the group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl,substituted aryl, heteroaryl, halogen, and substituted heteroaryl;

R^(5a) is H, —CN, CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j); wherein Pg^(2j) is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) _(an)dR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R¹¹ is H, alkyl, —COCH₃, or a hydroxyl protecting group;

N^(1j) is —NHPg^(1j), —NH₂, or N₃, wherein Pg^(1j) is an aminoprotecting group;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3.

The present disclosure provides a compound of formula AB-4:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵ and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X⁴ is selected from the group consisting of H, NH₂, N₃, protected aminogroup, OH, —OPg^(2k), and halogen; wherein Pg^(2k) is a hydroxylprotecting group;

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl; wherein thealkyl is unsubstituted or substituted with one or more substituentsselected from the group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl,substituted aryl, heteroaryl, halogen, and substituted heteroaryl;

R^(5a) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —NH₂, —CN, CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j);

wherein Pg^(2j) is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(49z), wherein R^(39z) _(an)dR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R¹¹ is H, alkyl, —COCH₃, or a hydroxyl protecting group;

N^(1m) is —NHPg^(1m), —NH₂, or N₃, wherein Pg^(1m) is an aminoprotecting group;

N^(1n) is —NHPg^(1n), —NH₂, or N₃, wherein Pg^(1n) is an aminoprotecting group;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3.

The present disclosure provides a compound of formula ABC-3:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(1a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X⁵ is selected from the group consisting of H, NH₂, N₃, protected aminogroup, OH, —OPg²¹, and halogen; wherein Pg²¹ is a hydroxyl protectinggroup;

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl; wherein thealkyl is unsubstituted or substituted with one or more substituentsselected from the group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl,substituted aryl, heteroaryl, halogen, and substituted heteroaryl;

R^(5a) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j);

wherein Pg^(2j) is a hydroxyl protecting group;

R^(7a), R^(7b), and R^(7c) are, independently, H, OH, —OR⁷¹ or —OPg²;

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl;

wherein Pg² is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

N^(1o) is —NHPg^(1o), —NH₂, or N₃, wherein Pg^(1o) is an aminoprotecting group;

N^(1p) is —NHPg^(1p), —NH₂, or N₃, wherein Pg^(1p) is an aminoprotecting group;

Pg^(2f) is a hydroxyl protecting group or H;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3.

The present disclosure provides a compound of formula ABCD-3:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X⁶ is selected from the group consisting of H, NH₂, N₃, protected aminogroup, OH, —OPg^(2m), and halogen; wherein Pg^(2m) is a hydroxylprotecting group;

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl;

wherein the alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, halogen, and substitutedheteroaryl;

R^(5a) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j); wherein Pg^(2j) is a hydroxyl protecting group;

R^(7a), R^(7b), and R^(7c) are, independently, H, OH, —OR⁷¹ or —OPg²;

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl;

wherein Pg² is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

N^(1q) is —NHPg^(1q) or N₃, wherein Pg^(1q) is an amino protectinggroup;

N^(1r) is —NHPg^(1r) or N₃, wherein Pg^(1r) is an amino protectinggroup;

N^(1g) is —NHPg^(1g) or N₃, wherein Pg^(1g) is an amino protectinggroup;

N^(1h) is —NHPg^(1h) or N₃, wherein Pg^(1h) is an amino protectinggroup;

Pg^(2g) is a hydroxyl protecting group;

Pg^(2h) is a hydroxyl protecting group;

wherein at least one of N^(1q)N^(1r), N^(1g), N^(1h) is not NH₂ orwherein at least one of PG^(2g) or Pg^(2h) is not H or wherein X⁶ is not—OH or —NH₂;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3.

In certain aspects, provided herein is a method for treating a bacterialinfection in a subject, comprising administering to a subject in needthereof a therapeutically effective amount of a compound of formulaeAB-2, ABC-2, AB-2′ or ABC-2′, or a pharmaceutically acceptable salt,solvate, stereoisomer, or tautomer thereof.

In still another aspect, provided is a method for treating a bacterialinfection in a subject, comprising administering to a subject in needthereof a therapeutically effective amount of a pharmaceuticalcomposition comprising a compound AB-2, AB-2′, AB-2″, ABC-2, ABC-2′, orABC-2″, or a pharmaceutically acceptable salt, solvate, stereoisomer, ortautomer thereof, and a pharmaceutically acceptable carrier.

In some variations of the provided methods, the bacterial infection is agram-negative bacterial infection. In certain variations, the bacterialinfection is infection of a Staphylococcus, Lactobacillus,Streptococcus, Sarcina, Escherichia, Enterobacter, Klebsiella,Pseudomonas, Acinetobacter, Mycobacterium, Proteus, Campylobacter,Citrobacter, Nisseria, Baccillus, Bacteroides, Peptococcus, Clostridium,Salmonella, Shigella, Serratia, Haemophilus, Brucella, Francisella,Anthracis, Yersinia, Corynebacterium, Moraxella, or Enterococcusspecies.

In yet a further aspect, provided herein is the use of a compound AB-2,AB-2′, AB-2″, ABC-2, ABC-2′, or ABC-2″, or a pharmaceutically acceptablesalt, solvate, stereoisomer, or tautomer thereof, in the manufacture ofa medicament for treating a bacterial infection in a subject in needthereof.

In still a further aspect, provided herein is a compound AB-2, AB-2′,AB-2″, ABC-2, ABC-2′, or ABC-2″, or a pharmaceutically acceptable salt,solvate, stereoisomer, or tautomer thereof, for use in a method oftreating a bacterial infection in a subject in need thereof.

The details of the disclosure are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent disclosure, illustrative methods and materials are nowdescribed. Other features, objects, and advantages of the disclosurewill be apparent from the description and from the claims. In thespecification and the appended claims, the singular forms also includethe plural unless the context clearly dictates otherwise. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art towhich this disclosure belongs. All patents and publications cited inthis specification are incorporated herein by reference in theirentireties.

Each embodiment described herein may be taken alone or in combinationwith any one or more other embodiments.

DETAILED DESCRIPTION OF THE DISCLOSURE

The present disclosure relates to novel methods for preparingantibacterial aminoglycoside compounds, as well as to relatedintermediates useful in such methods.

As discussed above, the present disclosure provides processes forpreparing compounds AB, ABC, and ABCD. The processes comprisecombinations of reactions and conditions that can provide certain novelintermediate compounds.

Scheme 1 shows a representation of preparation of compounds AB, ABC, andABCD.

The articles “a” and “an” as used in this disclosure may refer to one ormore than one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

As used in this disclosure, “and/or” may mean either “and” or “or”unless indicated otherwise.

As used herein,

may refer to a single bond or a double bond.

“Alkyl” may refer to a straight or branched chain saturated hydrocarbon.C₁-C₃alkyl groups contain 1 to 3 carbon atoms. Examples of a C₁-C₃alkylgroup include, but are not limited to, methyl, ethyl, and propyl.

The term “protecting group,” as used herein, may refer to a labilechemical moiety which is known in the art to protect reactive groupsincluding without limitation, hydroxyl and amino groups, againstundesired reactions during synthetic procedures. Hydroxyl and aminogroups which protected with a protecting group are referred to herein as“protected hydroxyl groups” and “protected amino groups”, respectively.Protecting groups are typically used selectively and/or orthogonally toprotect sites during reactions at other reactive sites and can then beremoved to leave the unprotected group as is or available for furtherreactions. Protecting groups as known in the art are described generallyin Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition,John Wiley & Sons, New York (1999). Groups may be selectivelyincorporated into aminoglycosides described herein as precursors. Forexample, an amino group can be placed into a compound described hereinas an azido group that can be chemically converted to the amino group ata desired point in the synthesis. Generally, groups are protected orpresent as a precursor that will be inert to reactions that modify otherareas of the parent molecule for conversion into their final groups atan appropriate time. Further, representative protecting or precursorgroups are discussed in Agrawal, et al., Protocols for OligonucleotideConjugates, Eds, Humana Press; New Jersey, 1994; Vol. 26 pp. 1-72.Examples of “hydroxyl protecting groups” include, but are not limitedto, t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl,p-chlorophenyl, 2,4-dinitrophenyl, benzyl, 2,6-dichlorobenzyl,diphenylmethyl, p-nitrobenzyl, triphenylmethyl, trimethylsilyl,triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl (TBDPS),triphenylsilyl, benzoylformate, acetate, chloroacetate,trichloroacetate, trifluoroacetate, pivaloate, benzoate,p-phenylbenzoate, 9-fluorenylmethyl carbonate, mesylate and tosylate.Examples of “amino protecting groups” include, but are not limited to,2-trimethyl-silylethoxycarbonyl (Teoc),1-methyl-1-(4-biphenylyl)ethoxycarbonyl (Bpoc), t-butoxycarbonyl (Boc),allyloxycarbonyl (Alloc), 9-fluorenylmethyloxycarbonyl (Fmoc),benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl (PNZ), formyl, acetyl,trihaloacetyl (e.g., trifluoroacetyl), benzoyl, nitrophenylacetyl,2-nitrobenzenesulfonyl, phthalimido, and dithiasuccinoyl.

A salt may also include acid addition salts. An “acid addition salt” mayrefer to those salts which retain the biological effectiveness andproperties of the freebases, which are not biologically or otherwiseundesirable, and which are formed with inorganic acids such as, but arenot limited to, hydrochloric acid, hydrobromic acid, sulfuric acid,nitric acid, phosphoric acid and the like, and organic acids such as,but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid,alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid,benzoic acid, 4-acetamidobenzoic acid, camphoric acid,camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid,carbonic acid, cinnamic acid, citric acid, cyclamic acid,dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaricacid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid,glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoricacid, glycolic acid, hippuric acid, isobutyric acid, lactic acid,lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid,mandelic acid, methanesulfonic acid, mucic acid,naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid,1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid,oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamicacid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid,stearic acid, succinic acid, tartaric acid, thiocyanic acid,p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and thelike.

The compounds described herein and the process of making the compoundsmay include solvates of the compounds described herein. The term“solvate” may refer to a complex of variable stoichiometry formed by asolute and solvent. Such solvents for the purpose of the disclosure maynot interfere with the biological activity of the solute. Examples ofsuitable solvents may include, but are not limited to, water, MeOH,EtOH, and AcOH. Solvates wherein water is the solvent molecule aretypically referred to as hydrates. Hydrates may include compositionscontaining stoichiometric amounts of water, as well as compositionscontaining variable amounts of water.

Those skilled in the art will recognize if a stereocenter exists in anyof the compounds described herein and the process of making thecompounds. Accordingly, the present disclosure includes both possiblestereoisomers (unless the stereochemistry is specified herein) andincludes not only racemic compounds but the individual enantiomersand/or diastereomers as well. Additionally, those skilled in the artwill recognize if a positional or geometric isomer exists for a compounddescribed herein. Accordingly, the present disclosure includes allpossible positional or geometric isomers (unless the isomer is specifiedherein). In the structures shown herein, where the stereochemistry ofany particular chiral atom is not specified or the geometric orpositional isomer is not specified, then all stereoisomers and geometricor positional isomers are contemplated and included in the compoundsdescribed herein and the process of making the compounds. Wherestereochemistry or geometric or positional isomer is specified, thenthat stereochemistry or geometric or position isomer is so specified anddefined.

The term “stereoisomers” may refer to the set of compounds which havethe same number and type of atoms and share the same bond connectivitybetween those atoms, but differ in three dimensional structure. The term“stereoisomer” may refer to any member of this set of compounds. Forinstance, a stereoisomer may be an enantiomer or a diastereomer. Thecompounds described herein and the process of making the compounds mayinclude stereoisomers.

The term “enantiomers” may refer to a pair of stereoisomers which arenon-superimposable mirror images of one another. The term “enantiomer”may refer to a single member of this pair of stereoisomers. The term“racemic” may refer to a 1:1 mixture of a pair of enantiomers. Thecompounds described herein and the process of making the compounds mayinclude enantiomers. Each compound herein disclosed may include all theenantiomers that conform to the general structure of the compound(unless the enantiomer is specified herein). The compounds may be in aracemic or enantiomerically pure form, or any other form in terms ofstereochemistry (unless the stereochemistry is specified herein). Insome embodiments the compounds are the (S)-enantiomer. In otherembodiments the compounds are the (R)-enantiomer. In yet otherembodiments, the compounds are the (+) or (−) enantiomers. In someembodiments, compounds described herein may be enriched to providepredominantly one enantiomer of a compound described herein. Anenantiomerically enriched mixture may comprise, for example, at least 60mol percent of one enantiomer, or more preferably at least 75, 80, 85,90, 95, 96, 97, 98, 99, 99.5 or even 100 mol percent. In someembodiments, the compound described herein enriched in one enantiomermay be substantially free of the other enantiomer, wherein substantiallyfree means that the substance in question makes up less than 10%, orless than 5%, or less than 4%, or less than 3%, or less than 2%, or lessthan 1% as compared to the amount of the other enantiomer, e.g., in thecompound mixture. For example, if a compound mixture contains 98 gramsof a first enantiomer and 2 grams of a second enantiomer, it would besaid to contain 98 mol percent of the first enantiomer and only 2 molpercent of the second enantiomer.

The term “diastereomers” may refer to the set of stereoisomers whichcannot be made superimposable by rotation around single bonds. Forexample, cis- and trans-double bonds, endo- and exo-substitution onbicyclic ring systems, and compounds containing multiple stereogeniccenters with different relative configurations are considered to bediastereomers. The term “diastereomer” may refer to any member of thisset of compounds. In some examples presented, the synthetic route mayproduce a single diastereomer or a mixture of diastereomers. Thecompounds described herein and the process of making the compounds mayinclude diastereomers. In some embodiments, the compounds describedherein may be enriched to provide predominantly one diastereomer of acompound disclosed herein. A diastereomerically enriched mixture maycomprise, for example, at least 60 mol percent of one diastereomer, ormore preferably at least 75, 99, 95, 96, 97, 98, 99, or even 100 molpercent.

In addition, the compounds described herein and the process of makingthe compounds include all geometric and positional isomers. For example,if a compound described herein incorporates a double bond or a fusedring, both the cis- and trans-forms, as well as mixtures, may beembraced within the scope of the disclosure. If the compound contains adouble bond, the substituent may be in the E or Z configuration (unlessthe configuration is specified herein). If the compound contains adisubstituted cycloalkyl, the cycloalkyl substituent may have a cis ortrans configuration (unless the configuration is specified herein).

The compounds described herein may further include all isotopicallylabeled compounds. An “isotopically” or “radio-labeled” compound is acompound where one or more atoms are replaced or substituted by an atomhaving an atomic mass or mass number different from the atomic mass ormass number typically found in nature (i.e., naturally occurring). Forexample, in some embodiments, in the compounds described herein hydrogenatoms may be replaced or substituted by one or more deuterium ortritium. Certain isotopically labeled compounds of this disclosure, forexample, those incorporating a radioactive isotope, may be useful indrug and/or substrate tissue distribution studies. The radioactiveisotopes tritium, i.e., ³H, and carbon 14, i.e., are particularly usefulfor this purpose in view of their ease of incorporation and ready meansof detection. Substitution with heavier isotopes such as deuterium,i.e., ²H, may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example, increased in vivo half-life orreduced dosage requirements, and hence may be preferred in somecircumstances. Suitable isotopes that may be incorporated in compoundsdescribed herein may include but are not limited to ²H (also written asD for deuterium), ³H (also written as T for tritium), ¹¹C, ¹³C, ¹⁴C,¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I,¹²⁴I, ¹²⁵I , and ¹³¹I. Substitution with positron emitting isotopes,such as ¹¹C, ¹⁸F, ¹⁵O, and ¹³N, may be useful in Positron Emission

Topography (PET) studies.

As described herein, compounds of the present disclosure may optionallybe substituted with one or more substituents, such as those illustratedgenerally herein, or as exemplified by particular classes, subclasses,and species of the present disclosure. In general, the term“substituted” refers to the replacement of a hydrogen atom in a givenstructure with a specified substituent. Combinations of substituentsenvisioned by the present disclosure are typically those that result inthe formation of stable or chemically feasible compounds.

The compounds of any of the formulae described herein may be prepared bymethods known in the art of organic synthesis as set forth in part bythe following synthetic schemes and examples in conjunction with theguidance provided herein. In the schemes described below, it isunderstood that protecting groups for sensitive or reactive groups maybe employed where necessary in accordance with general principles orchemistry in accordance with the guidance provided herein. Protectinggroups may be manipulated according to standard methods of organicsynthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis,” Third edition, Wiley, New York 1999). These groups may beremoved at a convenient stage of the compound synthesis using methodsthat are readily apparent to those skilled in the art based on thedetailed teaching provided herein. The selection processes, as well asthe reaction conditions and order of their execution, shall beconsistent with the present disclosure.

Preparation of Compounds AB, ABC, and ABCD

As discussed above, the present disclosure provides processes forpreparing compounds AB, ABC, and ABCD (described in greater detailbelow). The processes comprise combinations of reactions and conditionsthat can provide certain novel intermediate compounds. Scheme 1 shows arepresentation of preparation of compounds AB, ABC, and ABCD.

Discussion of the preparation of protected activated A and protectedactivated B is provided below. Then, discussion of the preparation ofcompound AB is provided. Thereafter, discussion of the preparation ofcompounds ABC and ABCD is provided.

The processes comprise reactions that can yield novel intermediatecompounds through a combination of reaction conditions and steps. Also,Scheme 1 provides a modular synthesis of aminosaccharides and provides asynthetic scheme that allows for ease of functionalizing the rings and adiversity of substituents. Compounds with modifications on the corecarbon backbone of the aminoglycosides can be prepared, which werepreviously unobtainable by methods of synthesis in the art. Compoundswith two, three, or four rings can be prepared and tested or screenedfor activity expeditiously.

The reactions in the Scheme 1 can be performed through chemicalreactions using standard synthetic chemistry procedures and practicesoptionally using reagents such as catalysts including, but not limitedto, Pd reagents, chiral ligands, and enzymes.

Conventional atom numbering for formulae AB, ABC, and ABCD is shownbelow. The A, B, C, and D rings are also identified below. Thestructures below are representive and are based on generic structures,such that the substituents are shown below for convenience. When aspecific carbon is referenced in the disclosure, the carbon isreferenced with the numbering shown below. For example, C-6′ or C6′refers to the exocyclic carbon on the A ring, labeled as 6′, as shownbelow.

In certain embodiments, conventional atom numbering for formulae AB,ABC, and ABCD is shown below in another format.

Preparation of Ring A

The present disclosure includes processes, methods, reagents, andintermediates for the synthesis of Ring A:

In Ring A, LVG¹ is a leaving group suitable of reacting with a reactantor a glycosyl acceptor, to form an interglycosidic linkage. Thestructure shown above for Ring A is representive and is based on ageneric structure, such that the substituents are shown above forconvenience. That is, the substituents shown above for Ring A are notlimited to the certain substituents recited above. Suitable substituentsfor Ring A are described herein.

A process for the preparation of a Ring A is illustrated in Scheme 2below and is discussed in greater detail herein.

As noted above and with reference to Scheme 2, the present disclosureprovides processes for preparing Ring A. The present disclosure providesa process for preparing a compound of formula A-5,

wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵,and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H, alkyl,amino protecting group, or hydroxyl protecting group; wherein the C₁-C₆alkyl or alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of aryl, halogen, —OR³⁰,—NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, —NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

N^(1a) is —NHPg^(1a), N(Pg^(1a))₂, or N₃, wherein each Pg^(1a) isindependently an amino protecting group;

X¹ is —F, —Cl, —Br, or I;

LVG¹ is a leaving group;

m is zero, 1, or 2;

n is zero, 1, or 2; and,

-   -   wherein m+n is 1, 2 or 3;

or a salt, solvate, enantiomer, or diastereomer thereof, comprising:

(a) contacting a compound of formula A-1:

or a salt, solvate, enantiomer, or diastereomer thereof, with a chiralauxiliary reagent to yield a compound of formula A-2:

or a salt, solvate, enantiomer, or diastereomer thereof,

wherein Xc is a chiral auxiliary group;

(b) contacting the compound of formula A-2 with a Grignard ororganolithium reagent to yield a compound of formula A-3:

or a salt, solvate, enantiomer, or diastereomer thereof,

(c) contacting the compound of formula A-3 with a halogen reagent inpresence of a nucleophile reagent (Nuc-1) to yield a compound of formulaA-4:

or a salt, solvate, enantiomer, or diastereomer thereof;

wherein

X¹ is F, —Cl, —Br, or —I;

Nuc-1 is LVG¹-M, wherein M is H, a metal cation, a non-metal cation, ora lone pair of electrons;

LVG¹ is a leaving group;

(d) exchanging the chiral auxiliary group for an amino protecting groupPg^(1a) in the compound of formula A-4 by reaction with an aminoprotecting group reagent to yield the compound of formula A-5:

or a salt, solvate, enantiomer, or diastereomer thereof,

wherein N^(1a) is -13 NHPg^(1a), N(Pg^(1a))₂, or N₃, wherein each Pg^(1a) is independently an amino protecting group.

Synthesis of Compound A-2

With continued reference to Scheme 2, compound A-1 is contacted with achiral auxiliary reagent to yield compound A-2, which has a chiralauxiliary group. The chiral auxiliary reagent provides a chiralauxiliary group for compound A-2.

A chiral auxiliary reagent means any chiral compound or optically activecatalyst, e.g. a compound comprising asymmetrically substituted carbonatoms or axially chiral compounds, or mixtures of chiral compoundsand/or optically active catalysts, which will improve the yield of acompound of A-2 with respect to its epimer. Said chiral auxiliaryreagent will thus be any compound which is capable of increasing thestereoselectivity in comparison to the yield or stereoselectivitywithout the chiral auxiliary reagent present or involved. Suitablechiral auxiliary reagents that contain a free amino group such astert-butanesulfinamide or (S)-1-amino-2-methoxymethylpyrrolidine (SAMP)and (R)-1-amino-2-methoxymethylpyrrolidine (RAMP) hydrazones or iminesformed using pseudoephedrine.

Synthesis of Compound A-3

With continued reference to Scheme 2, compound A-2 is contacted with aGrignard or organolithium reagent to yield compound A-3. The Grignard ororganolithium reagent provides R^(1a) and/or R^(1b) substituents oncompound A-3. Thus, the Grignard or organolithium reagent corresponds toR^(1a) and/or R^(1b) moieties. In certain embodiments, R^(1b) ishydrogen.

In certain embodiments, the addition reaction in Scheme 3 can be carriedout using a Grignard reagent of formula: R^(1a)MgX, where R^(1a) is asdefined herein for general formula A-5 and X is a halide. In certainembodiments, the addition reaction in Scheme 3 can be carried out usingan organolithium reagent of formula: R^(1a)—Li, where R^(1a) is asdefined herein for general formula A-5.

A Grignard reagent of formula: R^(1a)MgX or an organolithium reagent offormula: R^(1a)—Li can be prepared from the corresponding halide ofR^(1a). A Grignard reagent is prepared by reaction of an organic halidewith magnesium An organolithium reagent is prepared by reaction of anorganic halide with lithium. For example, Grignard reagent ororganolithium reagent such as MeMgBr, EtMgBr, MeLi, or EtLi wouldprovide substituents, such as methyl or ethyl.

Synthesis of Compound A-4

With continued reference to Scheme 2, compound A-3 is contacted with ahalogen reagent in the presence of a nucleophile reagent (Nuc-1) toyield compound A-4. A halonium ion formation can occur from the reactionof the alkene of compound A-3 with the halogen reagent. Subsequently, anucleophilic reaction can open up the halonium ion to provide X¹ andLVG¹ substituents on compound A-4.

A halogen reagent can provide the halo group (e.g., X¹) on compound A-4at C2′, e.g., —F, —Cl, —Br, and —I. Examples of halogen reagents forreaction with compound A-3 include Cl₂, BR₂, NBS, NIS, HOC1, DAST, orI₂.

A nucleophilic reaction can open up the halonium ion to provide X¹ andLVG¹ substituents on compound A-4. A nucleophile reagent provides theLVG¹ substituent on compound A-4 at C1′. The LVG¹ substituent is aleaving group, such that Ring A becomes a glycosyl donor. In certainembodiments, LVG¹ is halo, OMs, OTs, OH, a thioalkyl, a thioaryl, animidate, an acetate, a phosphate, or an O-pentenyl group. A nucleophilicreagent can be prepared from the corresponding protonated or saltversion of LVG¹. For example, in certain embodiments, LVG¹ is —OH andthe corresponding nucleophilic reagent (Nuc-1) is water. Reaction withwater provides —OH as the substituent for LVG¹.

Synthesis of Compound A-5

With continued reference to Scheme 2, the chiral auxiliary group incompound A-4 is exchanged for an amino protecting group Pg^(l)a to yieldcompound A-5.

Removal of the chiral auxiliary group is conventional and depends on theidentity of the chiral auxiliary group. Examples include hydrolysisunder conditions such as base (for example, NaOH, KOH, Et₃N) or acidmediated (for example, HC1, TfOH, p-TSA) in aqueous media optionallyincluding oraganic solvents (for example, MeOH, Et₂O, DMF) attemperatures between 0° C. and the reflux point of the solvent; orhydrogenolysis under conditions such as an H2 atmosphere at pressuresranging from 1-10 ATM, in a solvent such as MeOH, DMF, EtOH atr roomtemperature.

Addition of amino protecting group Pg^(1a) to yield compound A-5 isprovided by an amino protecting group reagent. Examples of aminoprotecting group Pg^(1a) include Bn, CBZ, and tert-butanesulfinamide.Suitable protecting group reagents to provide amino protecting groupPg^(1a) can be found in “Protective Groups in Organic Synthesis, 4thEd”, Wiley-Interscience, Inc., 2007 (Theodora W. Greene, Peter G. M.Wuts); “Protecting Groups 3rd Ed.” Thieme, 2004 (P. J. Kocienski). Incertain embodiments, N^(1a) is N₃.

In certain embodiments, the chiral auxiliary can act as a protectinggroup. Thus, in certain embodiments, Pg^(l)a can includetert-butanesulfinamide or (S)-1-amino-2-methoxymethylpyrrolidine (SAMP)and (R)-1-amino-2-methoxymethylpyrrolidine (RAMP) hydrazones or iminesformed using pseudoephedrine.

In certain embodiments, compound A-5 can be used in the glycosylationreaction with a B ring.

In certain embodiments, compound A-5 can be hydrodehalogenated and thenused in the glycosylation reaction with a B ring. In such instances, X¹is converted to hydrogen. Examples of hydrodehalogenation reactionsinclude use of metal catalysts, such as transition metal catalyst,alkali and alkaline-earth metals.

In certain embodiments, in compound A-5, R^(2a), R^(2b), R^(3a) andR^(3b) are independently selected from the group consisting of H, OR²⁷,NR²⁸R²⁹ halogen, C₁-C₄ cycloalkyl, and C₁-C₆ alkyl, wherein each R²⁷,R²⁸, and R²⁹ is independently H, alkyl; wherein the C₁-C₆ alkyl or alkylis unsubstituted or substituted with one or more substituents selectedfrom the group consisting of halogen, —OR³⁰, —NR³¹R³², SR³³, and—SO₂R³⁴.

In certain embodiments, in compound A-5, N^(1a) is —NHPg^(1a) or N₃,wherein Pg^(1a) is an amino protecting group.

Synthesis of Compound A-6

In some embodiments, compound A-5 is converted to a compound A-6, asdescribed in Scheme 3.

With reference to Scheme 3a, when X¹ is not —NH₂, —N₃, a protected aminogroup, —OH, or protected hydroxyl group, the process further comprisesafter step (d):

(e) converting X¹ in the compound of formula A-5 to X to yield acompound of formula A-6:

or a salt, solvate, enantiomer, or diastereomer thereof;

wherein X is —NH₂, —N₃, a protected amino group, —OH, or protectedhydroxyl group.

For example, in certain embodiments, X¹ is halo. For this example, thehalo of X¹ is displaced with an azide (—N₃), which is then left alone orconverted to an amine through a reduction reaction. If X¹ becomes anamino group, the amino group can be further protected.

For example, in certain embodiments, the halo of X¹ is displaced with asource of —OH. In certain embodiments, a source of —OH is NaOH or KOH ina solvent such as DMF or MeOH at temperatures between 0° C. and thereflux point of the solvent. If X¹ becomes an hydroxyl group, thehydroxyl group can be further protected.

Additional Synthesis of Compound A-6

In some embodiments, compound A-5 is converted to a compound A-6, asdescribed in Scheme 3b. Scheme 3b also shows a transformation ofcompound A-5 to compound A-6 and details intermediate steps of oxidationand reduction.

With reference to Scheme 3b, when X¹ is not —NH₂, —N₃, a protected aminogroup, —OH, or protected hydroxyl group, the process further comprisesafter step (d):

(e2) oxidizing the LVG¹ of formula A-5 to yield a compound of formulaA-5y, wherein the compound of formula A-5y comprises an oxo group;

(e3) converting X¹ in a compound of formula A-5y to X to yield acompound of formula A-5z; and

(e4) reducing the oxo group in the compound of formula A-5z to LVG¹ toyield a compound of formula A-6;

or a salt, solvate, enantiomer, or diastereomer thereof;

wherein X is —NH₂, —N₃, a protected amino group, —OH, or protectedhydroxyl group.

In Scheme 3b, step (e2) is an oxidation step to convert the LVG¹ to anoxo group. For example, in certain embodiments for step (e2), anoxidation can be performed in the presence of pyridinium chlorochromate(PCC), pyridinium dichromate (PDC), Dess-martin periodinane (DMP) orSwern oxidation conditions in the solvents such as dichloromethane (DCM)or the like. In certain embodiments, LVG¹ is hydroxyl and the oxidationis performed in the presence of PDC in dichloromethane.

In Scheme 3b, for example, in certain embodiments for step (e3), X¹ ishalo. For this example, the halo of X¹ is displaced with an azide (—N₃),which is then left alone or converted to an amine through a reductionreaction. If X¹ becomes an amino group, the amino group can be furtherprotected.

In Scheme 3b, for example, in certain embodiments for step (e3), thehalo of X¹ is displaced with a source of —OH. In certain embodiments, asource of —OH is NaOH or KOH in a solvent such as DMF or MeOH attemperatures between 0° C. and the reflux point of the solvent. If X¹becomes an hydroxyl group, the hydroxyl group can be further protected.

In Scheme 3b, step (e4) is a reduction step to convert the oxo group toLVG¹. For example, in certain embodiments for step (e4), a reduction canbe performed in the presence of a reducing agent. Examples of reducingagents include hydrogen gas (H₂) and hydride reagents such asborohydrides, lithium aluminium hydride, diisobutylaluminium hydride(DIBAL-H) and lithium triethylborohydride.

Additional Preparation of Ring A

An additional process for the preparation of a Ring A is illustrated inScheme 4 below and is discussed in greater detail herein.

As noted above, the present disclosure provides processes for preparingRing A. The present disclosure provides a process for preparing aprocess for preparing a compound of formula A-5a,

wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵ and —OR¹⁶;

R^(2a), R^(2b), and R^(3a) are independently selected from the groupconsisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, and C₁-C₆alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H, alkyl, aminoprotecting group, or hydroxyl protecting group; wherein the C₁-C₆ alkylor alkyl is unsubstituted or substituted with one or more substituentsselected from the group consisting of aryl, halogen, —OR³⁰, —NR³¹R³²,—SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3b) is H;

N¹ is —NHPg^(1b), N(Pg^(1b))₂,or N₃, wherein each Pg^(1b) isindependently an amino protecting group;

X² is —F, —Cl, —Br, or I;

LVG² is a leaving group.

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

or a salt, solvate, enantiomer, or diastereomer thereof, comprising:

(a) converting —OH in the compound of formula A-7

or a salt, solvate, enantiomer, or diastereomer thereof, to R^(3a) toyield a compound of formula A-8:

or a salt, solvate, enantiomer, or diastereomer thereof, wherein

(b) contacting the compound of formula A-8 with a halogen reagent inpresence of a nucleophile reagent (Nuc-2) to yield a compound of formulaA-5a:

or a salt, solvate, enantiomer, or diastereomer thereof;

wherein

X² is —F, —Cl, —Br, or —I;

Nuc-2 is LVG²-M, wherein M is H, a metal cation, a non-metal cation, ora lone pair of electrons;

LVG² is a leaving group.

Synthesis of Compound A-8

With continued reference to Scheme 4, the hydroxyl group of compound A-7is converted to R^(3a) to yield a compound of formula (A-8). As shownabove, R^(3b) is hydrogen.

In certain embodiments, the hydroxyl group of compound A-7 is convertedto a halo group for R^(3a). For example, compound A-7 is contacted witha halogenating reagent. For example, DAST or Dexa-Fluor can be used toconvert a hydroxyl group to a fluoro group. For example, thionylchloride or the Appel reaction (PPh₃ and CCl₄) can be used to convert ahydroxyl group to a chloro group. For example, PBr₃, SOBr₂, or the Appelreaction (PPh₃ and CBr₄) can be used to convert a hydroxyl group to abromo group. For example, the Appel reaction (PPh₃, iodine andimidazole) can be used to convert a hydroxyl group to a iodo group.

In certain embodiments, the hydroxyl group of compound A-7 is convertedto an amino group for R^(3a). Suitable reactions that can convert ahydroxyl group to an amino group include the Gabriel synthesis andMitsonobu reaction (using an amine nucleophile).

In certain embodiments, the hydroxyl group of compound A-7 is convertedto an alkyl group for R^(3a). Suitable reactions that can convert ahydroxyl group to an alkyl group include transformation of the aboveproduced halogen containing derivatives under metalating condition suchas treatment of the halogen containing derivative with n-Bu-Li or Mgfollowed by treatment with an alkylating reagent RX such as MeI or EtClin solvents such as DCM or Et₂O at temperatures ranging from −78° C. toroom temperature.

Synthesis of Compound A-5a

With continued reference to Scheme 4, compound A-8 is contacted with ahalogen reagent in the presence of a nucleophile reagent (Nuc-2) toyield compound A-5a. A halonium ion formation can occur from thereaction of the alkene of compound A-8 with the halogen reagent.Subsequently, a nucleophilic reaction can open up the halonium ion toprovide X² and LVG² substituents on compound A-5a.

A halogen reagent can provide the halo group (e.g., X²) on compound A-5aat C2′, e.g., —F, —Cl, —Br, and —I. Examples of halogen reagents forreaction with compound A-8 include Cl₂, Br₂, NBS, NIS, HOCl, DAST, or I₂

A nucleophilic reaction can open up the halonium ion to provide X² andLVG² substituents on compound A-8. A nucleophile reagent provides theLVG² substituent on compound A-8 at C1′. The LVG² substituent is aleaving group, such that Ring A becomes a glycosyl donor. In certainembodiments, LVG² is halo, OMs, OTs, OH, a thioalkyl, a thioaryl, animidate, an acetate, a phosphate, or an O-pentenyl group. A nucleophilicreagent can be prepared from the corresponding protonated or saltversion of LVG². For example, in certain embodiments, LVG² is —OH andthe corresponding nucleophilic reagent (Nuc-2) is water. Reaction withwater provides —OH as the substituent for LVG².

In certain embodiments, compound A-5a can be used in the glycosylationreaction with a B ring.

In certain embodiments, compound A-5a can be hydrodehalogenated and thenused in the glycosylation reaction with a B ring. In such instances, X²is converted to hydrogen. Examples of hydrodehalogenation reactionsinclude use of metal catalysts, such as transition metal catalyst,alkali and alkaline-earth metals.

In certain embodiments, in compound A-5a, R^(2a), R^(2b), R^(3a) andR^(3b) are independently selected from the group consisting of H, —OR²⁷,—NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, and C₁-C₆ alkyl, wherein each R²⁷,R²⁸, and R²⁹ is independently H, alkyl; wherein the C₁-C₆ alkyl or alkylis unsubstituted or substituted with one or more substituents selectedfrom the group consisting of halogen, —OR³⁰, —NR³¹R³², —SR³³, and—SO₂R³⁴.

In certain embodiments, in compound A-5a, N^(1b) is —NHPg^(1b) or N₃,wherein Pg^(1b) is an amino protecting group.

Synthesis of Compound A-6a

In some embodiments, compound A-5a is converted to a compound A-6a, asdescribed in Scheme 5.

With reference to Scheme 5, wherein when X¹ is not —NH₂, —N₃, aprotected amino group, —OH, or protected hydroxyl group, furthercomprising after step (b):

(c) converting X² in the compound of formula A-5a to X to yield acompound of formula A-6a:

or a salt, solvate, enantiomer, or diastereomer thereof;

wherein X is —NH₂, —N₃, a protected amino group, —OH, or protectedhydroxyl group.

For example, in certain embodiments, X² is halo. For this example, thehalo of X² is displaced with an azide (—N₃), which is then left alone orconverted to an amine through a reduction reaction. If X² becomes anamino group, the amino group can be further protected.

For example, in certain embodiments, the halo of X² is displaced with asource of —OH. In certain embodiments, a source of —OH is NaOH or KOH ina solvent such as DMF or MeOH at temperatures between 0° C. and thereflux point of the solvent. If X² becomes an hydroxyl group, thehydroxyl group can be further protected.

Additional Synthesis of Compound A-6a

In some embodiments, compound A-5a is converted to a compound A-6a, asdescribed in Scheme 5b. Scheme 5b also shows a transformation ofcompound A-5a to compound A-6a and details intermediate steps ofoxidation and reduction.

With reference to Scheme 5b, when X² is not —NH₂, —N₃, a protected aminogroup, —OH, or protected hydroxyl group, the process further comprisesafter step (b):

(c2) oxidizing the LVG² of formula A-5a to yield a compound of formulaA-5w, wherein the compound of formula A-5w comprises an oxo group;

(c3) converting X² in a compound of formula A-5w to X to yield acompound of formula A-5x; and

(c4) reducing the oxo group in the compound of formula A-5x to LVG² toyield a compound of formula A-6a;

or a salt, solvate, enantiomer, or diastereomer thereof;

wherein X is —NH₂, —N₃, a protected amino group, —OH, or protectedhydroxyl group.

In Scheme 5b, step (c2) is an oxidation step to convert the LVG² to anoxo group. For example, in certain embodiments for step (c2), anoxidation can be performed in the presence of pyridinium chlorochromate(PCC), pyridinium dichromate (PDC), Dess-martin periodinane (DMP) orSwern oxidation conditions in the solvents such as dichloromethane (DCM)or the like. In certain embodiments, LVG² is hydroxyl and the oxidationis performed in the presence of PDC in dichloromethane.

In Scheme 5b, for example, in certain embodiments for step (c3), X² ishalo. For this example, the halo of X² is displaced with an azide (—N₃),which is then left alone or converted to an amine through a reductionreaction. If X² becomes an amino group, the amino group can be furtherprotected.

In Scheme 5b, for example, in certain embodiments for step (c3), thehalo of X² is displaced with a source of —OH. In certain embodiments, asource of —OH is NaOH or KOH in a solvent such as DMF or MeOH attemperatures between 0° C. and the reflux point of the solvent. If X²becomes an hydroxyl group, the hydroxyl group can be further protected.

In Scheme 5b, step (c4) is a reduction step to convert the oxo group toLVG². For example, in certain embodiments for step (c4), a reduction canbe performed in the presence of a reducing agent. Examples of reducingagents include hydrogen gas (H₂) and hydride reagents such asborohydrides, lithium aluminium hydride, diisobutylaluminium hydride(DIBAL-H) and lithium triethylborohydride.

Additional Embodiments of Ring A

In certain embodiments, Ring A at the 6′-position can be OH. In suchinstances, the A ring with a hydroxyl group at the 6′-position can becommercially available or prepared with techniques known in the art. Forexample, compounds A-5 and A-5a herein are shown below as A-5″ andA-5a″, wherein N^(1a) is —OH, protected hydroxyl group, —NHPg^(1a),—N(Pg^(1a))₂, or N₃, wherein each Pg^(1a) is independently an aminoprotecting group and wherein N^(1b) is —OH, protected hydroxyl group,—NHPg^(1b), —N(Pg^(1b))₂, or N₃, wherein each Pg^(1a) is independentlyan amino protecting group.

Embodiments of Ring A

In certain embodiments, the stereochemistry in the ring of formulae A-1,A-2, A-3, A-4, A-5, A-5a, A-6, A-6a, A-7, and A-8 is as indicated informula (A′), wherein

is a single bond or a double bond and wherein

indicates a point of attachment to a hydrogen or a moiety:

In certain embodiments, m is one. In certain embodiments, n is one. Incertain embodiments, m is one and n is one.

Preparation of Ring B

The present disclosure includes processes, methods, reagents, andintermediates for the synthesis of Ring B:

In Ring B, the hydroxyl group at C5 is group suitable of reacting with areactant or a glycosyl donor, to form an interglycosidic linkage. Thestructure shown above for Ring B is representive and is based on ageneric structure, such that the substituents are shown above forconvenience. That is, the substituents shown above for Ring B are notlimited to the certain substituents and suitable substituents for Ring Bare described herein.

A process for the preparation of a Ring B is illustrated in Schemes 6and 6a below and is discussed in greater detail herein.

As noted above, the present disclosure provides processes for preparingRing B. With reference to Scheme 6, the present disclosure provides aprocess for preparing a compound of formula B-6,

wherein

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl; wherein thealkyl is unsubstituted or substituted with one or more substituentsselected from the group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl,substituted aryl, heteroaryl, halogen, and substituted heteroaryl;

R⁵ is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl is unsubstitutedor substituted with one or more substituents selected from the groupconsisting of —OH, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2o); wherein Pg^(2o) is a hydroxyl protecting group;

R⁸ is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

N^(1c) is —NHPg^(1c) or N₃, wherein Pg^(1c) is an amino protectinggroup;

Pg^(2b) is a hydroxyl protecting group;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

or a salt, solvate, enantiomer, or diastereomer thereof, comprising:

(a) contacting a compound of formula B-1:

or a salt, solvate, enantiomer, or diastereomer thereof, with an aminoprotecting group reagent and a hydroxyl protecting group reagent toyield a compound of formula B-2:

or a salt, solvate, enantiomer, or diastereomer thereof;

wherein Pg^(2a) is a hydroxyl protecting group;

(b) converting the amino group of the compound of formula B-2 at C1 toan azide group;

(c) converting the azide group of the compound of formula B-2 at C1 to ahydroxyl group;

(d) oxidizing the hydroxyl group of the compound of formula B-2 at C1 toan oxo group to yield a compound of formula B-3:

or a salt, solvate, enantiomer, or diastereomer thereof;

(e) converting the oxo group of the compound of formula B-3 to an iminogroup and contacting with an amino reactive reagent to yield a compoundof formula B-4:

or a salt, solvate, enantiomer, or diastereomer thereof;

(f) contacting the compound of formula B-4 with a Grignard ororganolithium reagent to yield a compound of formula B-5:

or a salt, solvate, enantiomer, or diastereomer thereof,

(g) forming a hydroxyl group by selective removal of the Pg^(2a)protecting group of the compound of formula B-5 to yield the compound offormula B-6:

or a salt, solvate, enantiomer, or diastereomer thereof.

A process for the preparation of a Ring B is illustrated in Scheme 6abelow and is discussed in greater detail herein.

As noted above, the present disclosure provides processes for preparingRing B. With reference to Scheme 6a, the present disclosure provides aprocess for preparing a compound of formula B-6′,

wherein

R^(4aa) and R^(4bb) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H, alkyl, —CONH₂, or—COCH₃; wherein the alkyl is unsubstituted or substituted with one ormore substituents selected from the group consisting of —CONH₂, —OH,—NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen, andsubstituted heteroaryl;

R^(5aa) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —OC(O)CH₃, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2o); wherein Pg^(2o) is a hydroxyl protecting group;

R⁸ is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(8b) is H or C₁-C₃alkyl;

N^(1c) is —NHPg^(1c) or N₃, wherein Pg^(1c) is an amino protectinggroup;

Pg^(2b) is a hydroxyl protecting group;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

or a salt, solvate, enantiomer, or diastereomer thereof, comprising:

(a) contacting a compound of formula B-1′:

or a salt, solvate, enantiomer, or diastereomer thereof, with an aminoprotecting group reagent and a hydroxyl protecting group reagent toyield a compound of formula B-2′:

or a salt, solvate, enantiomer, or diastereomer thereof;

wherein Pg^(2a) is a hydroxyl protecting group;

(b) converting the amino group of the compound of formula B-2′ at C1 toan azide group;

(c) converting the azide group of the compound of formula B-2′ at C1 toa hydroxyl group;

(d) oxidizing the hydroxyl group of the compound of formula B-2′ at C1to an oxo group to yield a compound of formula B-3′:

or a salt, solvate, enantiomer, or diastereomer thereof; (e) convertingthe oxo group of the compound of formula B-3′ to an imino group andcontacting with an amino reactive reagent to yield a compound of formulaB-4′:

or a salt, solvate, enantiomer, or diastereomer thereof;

(f) contacting the compound of formula B-4′ with a Grignard ororganolithium reagent to yield a compound of formula B-5′:

or a salt, solvate, enantiomer, or diastereomer thereof,

(g) forming a hydroxyl group by selective removal of the Pg^(2a)protecting group of the compound of formula B-5′ to yield the compoundof formula B-6′:

or a salt, solvate, enantiomer, or diastereomer thereof.

Synthesis of Compound B-2

Reference to compounds B-1 to B-6 are meant to encompass compounds B-1′to B-6′. With reference to Schemes 6 and 6a, compound B-1 is contactedwith an amino protecting group reagent and a hydroxyl protecting groupreagent to yield a compound B-2.

Addition of amino protecting group Pg^(1c) to yield compound B-2 isprovided by an amino protecting group reagent. Examples of aminoprotecting group Pg^(2a) include, but are not limited to,2-trimethylsilylethoxycarbonyl (Teoc),1-methyl-1-(4-biphenylyl)ethoxycarbonyl (Bpoc), t-butoxycarbonyl (Boc),allyloxycarbonyl (Alloc), 9-fluorenylmethyloxycarbonyl (Fmoc),benzyl-oxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl (PNZ), formyl,acetyl, trihaloacetyl (e.g., trifluoroacetyl), benzoyl,nitrophenylacetyl, 2-nitrobenzenesulfonyl, phthalimido, anddithiasuccinoyl. Suitable protecting group reagents to provide aminoprotecting group Pg^(2a) can be found in “Protective Groups in OrganicSynthesis, 4th Ed”, Wiley-Interscience, Inc., 2007 (Theodora W. Greene,Peter G. M. Wuts); “Protecting Groups 3rd Ed.” Thieme, 2004 (P. J.Kocienski).

Addition of hydroxyl protecting groups Pg^(2a) and Pg^(2b) to yieldcompound B-2 is provided by hydroxyl protecting group reagents. Examplesof hydroxyl protecting group Pg^(2a) and Pg^(2b) include t-butyl,t-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl,1-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl, p-chlorophenyl,2,4-dinitrophenyl, benzyl, 2,6-dichlorobenzyl, diphenylmethyl,p-nitrobenzyl, triphenylmethyl, trimethylsilyl, triethylsilyl,t-butyldimethylsilyl, t-butyldiphenylsilyl (TBDPS), triphenylsilyl,benzoylformate, acetate, chloroacetate, trichloroacetate,trifluoroacetate, pivaloate, benzoate, p-phenylbenzoate,9-fluorenylmethyl carbonate, mesylate and tosylate. Suitable protectinggroup reagents to provide hydroxyl protecting groups Pg^(2a) and Pg^(2b)can be found in “Protective Groups in Organic Synthesis, 4th Ed”,Wiley-Interscience, Inc., 2007 (Theodora W. Greene, Peter G. M. Wuts);“Protecting Groups 3rd Ed.” Thieme, 2004 (P. J. Kocienski).

Synthesis of Compound B-3

With continued reference to Schemes 6 and 6a, the amino group ofcompound B-2 is converted to an azide, then displaced with a hydroxylgroup, and then the hydroxyl group is oxidized to an oxo group to yieldcompound B-3.

The amino group of the compound B-2 at C1 to an azide group. Suitablereactions that convert an amino group to an azide group include the useof an azide donor such as TfN₃ or NaN₃ in solvents such as MeOH or DMFat temperatures below 0° C.

The azide group of the compound B-2 at C1 is converted to a hydroxylgroup. Suitable reactions that convert an azide group to a hydroxylgroup include displacement of the azide by an OH— source such as NaOH orKOH is a solvent such as DMF or MeOH at temperatures between 0° C. andthe reflux point of the solvent.

The hydroxyl group of the compound B-2 at C1 is converted to an oxogroup by oxidizing the hydroxyl group of the compound B-2 at C1 to yielda compound B-3. Suitable reactions that convert an hydroxyl group to aoxo group include Swern oxidation, Jones oxidation, Dess-Martinoxidation, and use of PCC (pyridinium chlorochromate).

Synthesis of Compound B-4

With continued reference to Schemes 6 and 6a, the oxo group of compoundB-3 is converted to an imino group. A suitable reaction that converts anoxo group to a imino group includes treatment with an amine in a solventsuch at PhMe or MeOH optionally under dehydrating conditions such asDean-Stark at temperatures between room temperature and the reflux pointof the solvent.

After conversion to an imino group, compound B-3 is contacted with anamino reactive reagent to yield compound B-4. The reaction providesfunctionalization of ═NH of B ring with R⁸ moiety. The amino reactivereagent provides R⁸ substituent on compound B-4. Thus, the aminoreactive reagent corresponds to R⁸ moiety.

In certain embodiments, R⁸ is an amino protecting group. Examples ofamino protecting groups include, but are not limited to,2-trimethylsilylethoxycarbonyl (Teoc),1-methyl-1-(4-biphenylyl)ethoxycarbonyl (Bpoc), t-butoxycarbonyl (Boc),allyloxycarbonyl (Alloc), 9-fluorenylmethyloxycarbonyl (Fmoc),benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl (PNZ), formyl, acetyl,trihaloacetyl (e.g., trifluoroacetyl), benzoyl, nitrophenylacetyl,2-nitrobenzenesulfonyl, phthalimido, and dithiasuccinoyl. Suitableprotecting group reagents to provide amino protecting group Pg^(2a) canbe found in “Protective Groups in Organic Synthesis, 4th Ed”,Wiley-Interscience, Inc., 2007 (Theodora W. Greene, Peter G. M. Wuts);“Protecting Groups 3rd Ed.” Thieme, 2004 (P. J. Kocienski).

In certain embodiments, R⁸ is H. In certain embodiments, R⁸ isC₁-C₆alkyl, In certain embodiments, R⁸ is methyl. In certainembodiments, R⁸ is ethyl.

In certain embodiments, R⁸ forms an amide with the imino group.Carboxylic acids corresponding to the R⁸ moiety can react with iminogroup on C1 of the B ring to provide the R⁸ substituent. In certaininstances, a catalyst or activating agent can assist with amideformation reaction.

In certain embodiments, R⁸ is

wherein Q¹ is NH, O, or S. In certain embodiments, Q¹ is NH. In certainembodiments, Q¹ is O. In certain embodiments, Q¹ is S. In certainembodiments, wherein when z is one, then R^(6z) and R^(37z) are nothalo.

In certain embodiments, R⁸ is

wherein z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N.

In other embodiments, R⁸ is

for example

In some embodiments, R^(35z) is H. In certain embodiments, each R^(36z)and R^(37z) are H. In certain embodiments, R^(38z) is H. In otherembodiments, R^(38z) is alkyl, for example C₁alkyl, C₂alkyl, or C₃alkyl.In other embodiments, R^(38z) is —C(═NH)NR³⁹R⁴⁰, for example —C(═NH)NH₂.In certain embodiments, R^(35z) and R^(38z), together with the atoms towhich they are attached, form a heterocycloalkyl group comprising atleast one N.

In some embodiments, z is an integer from 0 to 4, from 0 to 3, from 0 to2, from 1 to 4, from 2 to 4, or from 1 to 3. In certain embodiments, zis 0, or z is 1, or z is 2, or z is 3, or z is 4.

In some embodiments, R⁸ is:

For example, R⁸ may be:

In some embodiments, R^(38z) is H. For example, R⁸ may be:

In some embodiments, R⁸ may be:

In some embodiments, R⁸ may be:

In certain embodiments, R⁸ is:

In certain embodiments, R⁸ is:

In certain embodiments, R⁸ is:

In other embodiments, at least one R^(36z) or R^(37z) is halogen. Forexample, in certain embodiments, R⁸ is:

wherein each R^(36z) and R^(37z) is independently halogen, for examplefluoro.

In certain embodiments, at least one R^(36z) or R^(37z) is halogen, andR^(38z) is H. For example, R⁸ may be:

wherein each R^(36z) and R^(37z) are independently halogen, for examplefluoro.

In other embodiments, at least one R^(36z) or R^(37z) is halogen. Forexample, in certain embodiments, R⁸ is:

wherein each R^(36z) and R^(37z) is independently halogen, for examplefluoro.

In certain embodiments, at least one R^(36z) or R^(37z) is halogen, andR^(38z) is H. For example, R⁸ may be:

wherein each R^(36z) and R^(37z) are independently halogen, for examplefluoro.

In other embodiments, R⁸ is

wherein at least one R^(36z) or R^(37z) is hydroxyl.

In other embodiments, R⁸ is

wherein at least one R^(36z) or R^(37z) is hydroxyl.

In some embodiments, R^(38z) is —C(═NH)NR^(39z)R^(40z), and R⁸ is:

In some embodiments, R^(39z) and R^(40z) are both H. In otherembodiments, R^(39z) and R^(40z) are both C₁-C₃alkyl. In still otherembodiments, one of R^(39z) and R^(40z) is H and the other isC₁-C₃alkyl.

R^(38z) may be —C(═NH)NH₂. Thus, in certain embodiments, R⁸ is:

In certain embodiments, R^(36z) and one R^(37z), together with the atomsto which they are attached, form a carbocylic ring having from 3 to 6ring atoms.

In certain embodiments, R^(8b) is H. In certain embodiments, R^(8b) isC₁-C₃alkyl.

Synthesis of Compound B-5

With continued reference to Schemes 6 and 6a, compound B-4 is contactedwith a Grignard or organolithium reagent to yield a compound B-5. Thereaction provides functionalization of C1 of B ring with R⁵ moiety. TheGrignard or organolithium reagent provides R⁵ substituent on compoundB-5. Thus, the Grignard or organolithium reagent corresponds to R⁵moiety.

In certain embodiments, the addition reaction in Schemes 6 and 6a can becarried out using a Grignard reagent of formula: R⁵MgX, where R⁵ is asdefined herein for general formula B-5 and X is a halide. In certainembodiments, the addition reaction in Schemes 6 and 6a can be carriedout using an organolithium reagent of formula: R⁵—Li, where R⁵ is asdefined herein for general formula B-5.

A Grignard reagent of formula: R⁵MgX or an organolithium reagent offormula: R⁵—Li can be prepared from the corresponding halide of R⁵.Depending on the functional groups on R⁵, various modifications for thereaction with a Grignard reagent or organolithium reagent can be used,including use of protecting groups.

A Grignard reagent is prepared by reaction of an organic halide withmagnesium An organolithium reagent is prepared by reaction of an organichalide with lithium. For example, Grignard reagent or organolithiumreagent such as MeMgBr, EtMgBr, MeLi, or EtLi would providesubstituents, such as methyl or ethyl.

Synthesis of Compound B-6

With continued reference to Schemes 6 and 6a, a selective removal of thePg^(2a) protecting group of the compound B-5 yields compound B-6, whichhas a hydroxyl group from the removal of the Pg^(2a) protecting group.Selective removal of Pg^(2a) protecting group can be performed byhydrolysis. For example, selective removal of Pg^(2a) protecting groupcan be performed by hydrolysis under conditions such as base (forexample, NaOH, KOH, Et₃N) or acid mediated (for example, HCl, TfOH,p-TSA) in aqueous media optionally including oraganic solvents (forexample, MeOH, Et₂O, DMF) at temperatures between 0° C. and the refluxpoint of the solvent.

Additional Preparation of Ring B

An additional process for the preparation of a Ring B is illustrated inSchemes 7, 7a, and 7b below and is discussed in greater detail herein.The atom numbering below is for a compound, where o and p are each one.

As noted above, the present disclosure provides processes for preparingRing B. With reference to Scheme 7, the present disclosure provides aprocess for preparing a process for preparing a compound of formulaB-11,

wherein

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl; wherein thealkyl is unsubstituted or substituted with one or more substituentsselected from the group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl,substituted aryl, heteroaryl, halogen, and substituted heteroaryl;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2o); wherein Pg^(2o) is a hydroxyl protecting group;

R⁸ is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

N^(1d) is —NHPg^(1d) or N₃, wherein Pg^(1d) is an amino protectinggroup;

Pg^(2d) is a hydroxyl protecting group;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

or a salt, solvate, enantiomer, or diastereomer thereof, comprising:

(a) contacting a compound of formula B-8:

or a salt, solvate, enantiomer, or diastereomer thereof, with an aminoprotecting group reagent and a first selective hydroxyl protecting groupreagent and a second selective hydroxyl protecting group reagent and anamino reactive reagent to yield a compound of formula B-9:

or a salt, solvate, enantiomer, or diastereomer thereof; wherein Pg^(2c)is a hydroxyl protecting group;

(b) contacting the compound of formula B-9 with a electrophilic reagentto yield a compound of formula B-10:

or a salt, solvate, enantiomer, or diastereomer thereof,

c) forming a hydroxyl group by selective removal of the Pg^(2c)protecting group of the compound of formula B-10 to yield the compoundof formula B-11:

or a salt, solvate, enantiomer, or diastereomer thereof.

A process for the preparation of a Ring B is illustrated in Schemes 7aand 7b below and is discussed in greater detail herein. Scheme 7b isScheme 7a, wherein N^(1s) is —NR⁸R^(8b). Also, for Scheme 7b, compoundB-8″ comprises —NH₂ for N^(1dx), in compound B-8′ in Scheme 7a.

As noted above, the present disclosure provides processes for preparingRing B. With reference to Schemes 7a and 7b, the present disclosureprovides a process for preparing a process for preparing a compound offormula B-11′,

wherein

R^(4aa) and R^(4bb) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H, alkyl, —CONH₂, or—COCH₃; wherein the alkyl is unsubstituted or substituted with one ormore substituents selected from the group consisting of —CONH₂, —OH,—NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen, andsubstituted heteroaryl;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2o); wherein Pg^(2o) is a hydroxyl protecting group;

N^(1s) is N₃ or —NR⁸R^(8b);

R⁸ is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(49z), wherein R^(39z) andR^(49z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(8b) is H or C₁-C₃alkyl;

N^(1d) is —NHPg^(1d) or N₃, wherein Pg^(1d) is an amino protectinggroup;

Pg^(2d) is a hydroxyl protecting group;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

or a salt, solvate, enantiomer, or diastereomer thereof, comprising:

(a) contacting a compound of formula B-8′:

or a salt, solvate, enantiomer, or diastereomer thereof, wherein N^(1dx)is —NH₂, —NHPg^(1d) or N₃, wherein Pg^(1d) is an amino protecting group,

with a first selective hydroxyl protecting group reagent; a secondselective hydroxyl protecting group reagent; an amino protecting groupreagent, if N^(1dx) is NH₂; and an amino reactive reagent, if N^(1s) is—NR⁸R^(8b), to yield a compound of formula B-9′:

or a salt, solvate, enantiomer, or diastereomer thereof; wherein Pg^(2c)is a hydroxyl protecting group;

(b) contacting the compound of formula B-9′ with a electrophilic reagentor oxidizing the alcohol at C6 to an oxo group and contacting the oxogroup with a nucleophilic reagent to yield a compound of formula B-10′:

or a salt, solvate, enantiomer, or diastereomer thereof,

c) forming a hydroxyl group by selective removal of the Pg^(2c)protecting group of the compound of formula B-10′ to yield the compoundof formula B-11′:

or a salt, solvate, enantiomer, or diastereomer thereof.

Synthesis of Compound B-9

Reference to compounds B-8 to B-11 are meant to encompass compounds B-8′to B-11′ and compounds B-8″ to B-11″. With continued reference toSchemes 7, 7a, and 7b, compound B-8 is contact with an amino protectinggroup reagent and a first selective hydroxyl protecting group reagentand a second selective hydroxyl protecting group reagent and an aminoreactive reagent to yield a compound B-9.

Addition of amino protecting group Pg^(1d) to yield compound B-9 isprovided by an amino protecting group reagent. Examples of aminoprotecting group Pg^(1d) include Bn, CBZ, and tert-butanesulfinamide.Suitable protecting group reagents to provide amino protecting groupPg^(1d) can be found in “Protective Groups in Organic Synthesis, 4thEd”, Wiley-Interscience, Inc., 2007 (Theodora W. Greene, Peter G. M.Wuts); “Protecting Groups 3rd Ed.” Thieme, 2004 (P. J. Kocienski). Incertain embodiments, N^(1d) is N₃. In certain embodiments, N^(1dx) isN₃.

In certain embodiments, N^(1s) is N₃. In such instances, the B ring withan azido group at the 1-position can be commercially available orprepared with techniques known in the art. In certain embodiments,N^(1s) is —NR⁸R^(8b).

Addition of hydroxyl protecting groups Pg^(2c) and Pg^(2d) to yieldcompound B-9 is provided by a hydroxyl protecting group reagent.Examples of hydroxyl protecting groups Pg^(2c) and Pg^(2d) includeinclude t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl,p-chlorophenyl, 2,4-dinitrophenyl, benzyl, 2,6-dichlorobenzyl,diphenylmethyl, p-nitrobenzyl, triphenylmethyl, trimethylsilyl,triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl (TBDPS),triphenylsilyl, benzoylformate, acetate, chloroacetate,trichloroacetate, trifluoroacetate, pivaloate, benzoate,p-phenylbenzoate, 9-fluorenylmethyl carbonate, mesylate and tosylate.Suitable protecting group reagents to provide hydroxyl protecting groupsPg^(2c) and Pg^(2d) can be found in “Protective Groups in OrganicSynthesis, 4th Ed”, Wiley-Interscience, Inc., 2007 (Theodora W. Greene,Peter G. M. Wuts); “Protecting Groups 3rd Ed.” Thieme, 2004 (P. J.Kocienski).

The reaction also provides functionalization of —NH₂ of B ring with R⁸moiety. The amino reactive reagent provides R⁸ substituent on compoundB-9. Thus, the amino reactive reagent corresponds to R⁸ moiety.

In certain embodiments, R⁸ is an amino protecting group. Examples ofamino protecting groups include, but are not limited to,2-trimethylsilylethoxycarbonyl (Teoc),1-methyl-1-(4-biphenylyl)ethoxycarbonyl (Bpoc), t-butoxycarbonyl (Boc),allyloxycarbonyl (Alloc), 9-fluorenylmethyloxycarbonyl (Fmoc),benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl (PNZ), formyl, acetyl,trihaloacetyl (e.g., trifluoroacetyl), benzoyl, nitrophenylacetyl,2-nitrobenzenesulfonyl, phthalimido, and dithiasuccinoyl. Suitableprotecting group reagents to provide amino protecting group Pg^(2a) canbe found in “Protective Groups in Organic Synthesis, 4th Ed”,Wiley-Interscience, Inc., 2007 (Theodora W. Greene, Peter G. M. Wuts);“Protecting Groups 3rd Ed.” Thieme, 2004 (P. J. Kocienski).

In certain embodiments, R⁸ is H. In certain embodiments, R⁸ isC₁-C₆alkyl, In certain embodiments, R⁸ is methyl. In certainembodiments, R⁸ is ethyl.

In certain embodiments, R⁸ forms an amide with the imino group.Carboxylic acids corresponding to the R⁸ moiety can react with iminogroup on Cl of the B ring to provide the R⁸ substituent. In certaininstances, a catalyst or activating agent can assist with amideformation reaction.

In certain embodiments, R⁸ is

wherein Q¹ is NH, O, or S. In certain embodiments, Q¹ is NH. In certainembodiments, Q¹ is O. In certain embodiments, Q¹ is S. In certainembodiments, wherein when z is one, then R^(36z) and R^(37z) are nothalo.

In certain embodiments, R⁸ is

wherein z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃alkyl; or

R³⁵z and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N.

In other embodiments, R⁸ is

for example

In some embodiments, R^(35z) is H. In certain embodiments, each R^(36z)and R^(37z) are H. In certain embodiments, R^(38z) is H. In otherembodiments, R^(38z) is alkyl, for example C₁alkyl, C₂alkyl, or C₃alkyl.In other embodiments, R^(38z) is —C(═NH)NR³⁹R⁴⁰, for example —C(═NH)NH₂.In certain embodiments, R^(35z) and R^(38z), together with the atoms towhich they are attached, form a heterocycloalkyl group comprising atleast one N.

In some embodiments, z is an integer from 0 to 4, from 0 to 3, from 0 to2, from 1 to 4, from 2 to 4, or from 1 to 3. In certain embodiments, zis 0, or z is 1, or z is 2, or z is 3, or z is 4.

In some embodiments, R⁸ is:

For example, R⁸ may be:

In some embodiments, R^(38z) is H. For example, R⁸ may be:

In some embodiments, R⁸ may be:

In some embodiments, R⁸ may be:

In certain embodiments, R⁸ is:

In certain embodiments, R⁸ is:

In certain embodiments, R⁸ is:

In other embodiments, at least one R^(36z) or R^(37z) is halogen. Forexample, in certain embodiments, R⁸ is:

wherein each R^(36z) and R^(37z) is independently halogen, for examplefluoro.

In certain embodiments, at least one R^(36z) or R^(37z) is halogen, andR^(38z) is H. For example, R⁸ may be:

wherein each R^(36z) and R^(37z) are independently halogen, for examplefluoro.

In other embodiments, at least one R^(36z) or R^(37z) is halogen. Forexample, in certain embodiments, R⁸ is:

wherein each R^(36z) and R^(37z) is independently halogen, for examplefluoro.

In certain embodiments, at least one R^(36z) or R^(37z) is halogen, andR^(38z) is H. For example, R⁸ may be:

wherein each R^(36z) and R^(37z) are independently halogen, for examplefluoro.

In other embodiments, R⁸ is

wherein at least one R^(36z) or R^(37z) is hydroxyl.

In other embodiments, R⁸ is

wherein at least one R^(36z) or R^(37z) is hydroxyl.

In some embodiments, R^(38z) is —C(═NH)NR^(39z)R^(40z), and R⁸ is:

In some embodiments, R^(39z) and R^(40z) are both H. In otherembodiments, R^(39z) and R^(40z) are both C₁-C₃alkyl. In still otherembodiments, one of R^(39z) and R^(40z) is H and the other isC₁-C₃alkyl.

R^(38z) may be —C(═NH)NH₂. Thus, in certain embodiments, R⁸ is:

In certain embodiments, R^(36z) and one R^(37z), together with the atomsto which they are attached, form a carbocylic ring having from 3 to 6ring atoms.

In certain embodiments, R^(8b) is H. In certain embodiments, R^(8b) isC₁-C₃alkyl.

Synthesis of Compound B-10

With continued reference to Schemes 7, 7a, and 7b, compound B-9 iscontacted with an electrophilic reagent to yield compound B-10. Thereaction provides functionalization of C6 of B ring with R^(6a) and/orR^(6b) moieties, as shown below.

In certain embodiments, the hydroxyl group is nucleophilic and can reactwith an electrophilic reagent. For example, an electrophilic reagentthat can provide an optionally substituted alkoxy for R^(h)a can be thecorresponding optionally substituted alkyl bearing a halide group. Inthis instance, the substituted alkyl attaches with the oxygen of thehydroxyl, while the halide serves as a leaving group for thenucleophilic reaction.

In certain embodiments, the alcohol at C6 of compound B-9 is oxidized toan oxo group and then the oxo group is contacted with a nucleophilicreagent.

In certain embodiments, R^(6b) is hydrogen. In certain embodiments,R^(6a) is an optionally substituted alkoxy. For example, in certainembodiments, R^(6a) is —OCH₃, —OCH₂CH₃, or —OCH₂CH₂NRR′, wherein R andR′ are independently alkyl.

Synthesis of Compound B-11

With continued reference to Schemes 7, 7a, and 7b, a selective removalof the Pg^(2c) protecting group of compound B-10 to yield compound B-11,which has a hydroxyl group resulting from the selective removal of thePg^(2c) protecting group. Selective removal of Pg^(2c) protecting groupcan be performed by hydrolysis. For example, selective removal ofPg^(2c) protecting group can be performed by hydrolysis under conditionssuch as base (for example, NaOH, KOH, Et₃N) or acid mediated (forexample, HCl, TfOH, p-TSA) in aqueous media optionally includingoraganic solvents (for example, MeOH, Et₂O, DMF) at temperatures between0° C. and the reflux point of the solvent.

Additional Embodiments of Ring B

In certain embodiments, Ring B at the 1-position can be —N₃. In suchinstances, the B ring with an azido group at the 1-position can becommercially available or prepared with techniques known in the art. Forexample, compounds B-6 and B-11 herein are shown below as B-6″ andB-11″, wherein N^(1s) is N₃ or —NR⁸R^(8b).

In certain embodiments, Ring B is protected at the 1 and 3 positions asa heterocyclic ring. In such instances, the B ring with 1 and 3positions protected as a heterocyclic ring can be commercially availableor prepared with techniques known in the art. For example, compounds B-6and B-11 herein are shown below as B-6′^(e) and B-11′^(e), wherein E isa 4-8 membered heterocyclic ring, that is unsubstituted or substitutedwith an oxo group.

For example, a B ring from B-6′^(e) and B-11′^(e) can be

wherein

indicates a point of attachment to a hydrogen or a moiety.

In certain embodiments, Ring B is protected at the 1 and 6 positions asa heterocyclic ring. In such instances, the B ring with 1 and 6positions protected as a heterocyclic ring can be commercially availableor prepared with techniques known in the art. For example, compounds B-6and B-11 herein are shown below as B-6′^(f) and B-11′^(f), wherein F isa 4-8 membered heterocyclic ring, that is unsubstituted or substitutedwith an oxo group.

For example, a B ring from B-6′^(f) and B-11′^(f) can be

wherein

indicates a point of attachment to a hydrogen or a moiety. In suchinstances, the F ring can be opened up and reacted to form the moietiesat the 1 and 6 positions in the B ring.

Embodiments of Ring B

In certain embodiments, the stereochemistry in the ring of formulae B-1,B-2, B-3, B-4, B-5, B-6, B-8, B-9, B-10, and B-11, is as indicated informula (B′), wherein

indicates a point of attachment to a hydrogen or a moiety:

In certain embodiments, the stereochemistry in the ring of formulaeB-1′, B-2′, B-3′, B-4′, B-5′, B-6′, B-8′, B-9′, B-10′, and B-11′, is asindicated in formula (B″), wherein

indicates a point of attachment to a hydrogen or a moiety:

In certain embodiments, o is one. In certain embodiments, p is one. Incertain embodiments, o is one and p is one.

Preparation of AB

The present disclosure includes processes, methods, reagents, andintermediates for the synthesis of Compound AB, as shown in Scheme 1.

In Ring A, LVG' is a leaving group suitable of reacting with a reactantor a glycosyl acceptor, to form an interglycosidic linkage. In Ring B,the hydroxyl group at C5 is group suitable of reacting with a reactantor a glycosyl donor, to form an interglycosidic linkage.

The structures shown above for Rings A and B are representive and arebased on a generic structure, such that the substituents are shown abovefor convenience. That is, the substituents shown above for Rings A and Bare not limited to the certain substituents and suitable substituentsfor Rings A and B are described herein.

A process for the preparation of compound AB-1 is illustrated in Schemes8, 8a, and 8b below and is discussed in greater detail herein.

With reference to Scheme 8, the present disclosure provides a processfor preparing a process for preparing a compound of formula AB-1,

wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵ and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, —NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl;

wherein the alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, halogen, and substitutedheteroaryl;

R^(5a) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2m); wherein Pg^(2m) is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

N^(1e) is —NHPg^(1e) or N₃, wherein Pg^(1e) is an amino protectinggroup;

N^(1f) is —NHPg^(1f) or N₃, wherein Pg^(1f) is an amino protectinggroup;

Pg^(2e) is a hydroxyl protecting group;

X is —NH₂, —N₃, protected amino group, —OH, or protected hydroxyl group;

m is zero, 1, or 2;

n is zero, 1, or 2;

wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2;

wherein q+r is 1, 2 or 3;

or a salt, solvate, enantiomer, or diastereomer thereof, comprising:

(a) contacting a compound of formula A-9:

wherein LVG³ is a leaving group,

with a compound of formula B-12:

to yield the compound of formula (AB-1).

A process for the preparation of compound AB-1′ is illustrated inSchemes 8a and 8b below and is discussed in greater detail herein.Scheme 8b is Scheme 8a, wherein N^(1s) is —NR^(8a)R^(8b).

With reference to Scheme 8a, the present disclosure provides a processfor preparing a process for preparing a compound of formula AB-1′,

wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H, alkyl,amino protecting group, or hydroxyl protecting group; wherein the C₁-C₆alkyl or alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of aryl, halogen, —OR³⁰,—NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(4aa) and R^(4bb) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H, alkyl, —CONH₂, or—COCH₃; wherein the alkyl is unsubstituted or substituted with one ormore substituents selected from the group consisting of —CONH₂, —OH,—NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen, andsubstituted heteroaryl;

R^(5aa) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —OC(O)CH₃, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2m); wherein Pg^(2m) is a hydroxyl protecting group;

N^(1s) is N₃ or —NR^(8a)R^(8b);

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(8b) is H or C₁-C₃alkyl;

N^(1e) is —OH, protected hydroxyl group, —NHPg^(1e), N(Pg^(1e))₂, or N₃,wherein each Pg^(1e) is independently an amino protecting group;

N^(1f) is —NHPg^(1f) or N₃, wherein Pg^(1f) is an amino protectinggroup;

Pg^(2e) is a hydroxyl protecting group;

X⁷ is H, —NH₂, —N₃, protected amino group, —OH, protected hydroxylgroup, or halogen;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3;

or a salt, solvate, enantiomer, or diastereomer thereof, comprising:

(a) contacting a compound of formula A-9′:

wherein LVG³ is a leaving group,

with a compound of formula B-12′:

to yield the compound of formula (AB-1′).

Synthesis of Compound AB-1

With reference to Scheme 8, compound A-9 is contacted with compound B-12to yield compound AB-1. In certain embodiments, compound A-9 is compoundA-5. In certain embodiments, compound A-9 is compound A-5a. In certainembodiments, compound B-12 is compound B-6. In certain embodiments,compound B-12 is compound B-11.

With reference to Scheme 8a, compound A-9′ is contacted with compoundB-12′ to yield compound AB-1′. Scheme 8b is Scheme 8a, wherein—NR^(8a)R^(8b). Reference to compounds A-9, B-12, and AB-1 herein aremeant to encompass compounds A-9′, A-9″, B-12′, B-12′, AB-1′, and AB-1″

The reaction is performed under to conditions to allow for chemicalglycosylation with coupling of a glycosyl donor and a glycosyl acceptor.In Scheme 8, a glycosyl donor (LVG³ on compound A-9) and a glycosylacceptor (—OH on compound B-12) are coupled. In certain embodiments,LVG³ is selected from the group consisting of OH, halides, thioalkylgroups, thioaryl groups, imidates, acetate, phosphate, and O-pentenylgroups. In certain embodiments, LVG³ is halo, OMs, OTs, OH, a thioalkyl,a thioaryl, an imidate, an acetate, a phosphate, or an O-pentenyl group.

In certain embodiments, a suitable activating reagent is provided toassist the chemical glycosylation reaction. In certain embodiments, BF3is used as an activating agent. In certain embodiments, standardglycosyl formation conditions include use of an activating agent, suchas BF₃.Et₂O or AlMe₃ in solvents such as MeOH or THF at temperaturesbetween 0° C. and room temperature.

In certain embodiments, R^(8a) is an amino protecting group. Examples ofamino protecting groups include, but are not limited to,2-trimethylsilylethoxycarbonyl (Teoc),1-methyl-1-(4-biphenylyl)ethoxycarbonyl (Bpoc), t-butoxycarbonyl (Boc),allyloxycarbonyl (Alloc), 9-fluorenylmethyloxycarbonyl (Fmoc),benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl (PNZ), formyl, acetyl,trihaloacetyl (e.g., trifluoroacetyl), benzoyl, nitrophenylacetyl,2-nitrobenzenesulfonyl, phthalimido, and dithiasuccinoyl. Suitableprotecting group reagents to provide amino protecting group Pg^(2a) canbe found in “Protective Groups in Organic Synthesis, 4th Ed”,Wiley-Interscience, Inc., 2007 (Theodora W. Greene, Peter G. M. Wuts);“Protecting Groups 3rd Ed.” Thieme, 2004 (P. J. Kocienski).

In certain embodiments, R^(8a) is H. In certain embodiments, R^(8a) isC₁-C₆alkyl, In certain embodiments, R^(8a) is methyl. In certainembodiments, R^(8a) is ethyl.

In certain embodiments, R^(8a) forms an amide with the imino group.Carboxylic acids corresponding to the R^(8a) moiety can react with iminogroup on C1 of the B ring to provide the R^(8a) substituent. In certaininstances, a catalyst or activating agent can assist with amideformation reaction.

In certain embodiments, R^(8a) is

wherein Q¹ is NH, O, or S. In certain embodiments, Q¹ is NH. In certainembodiments, Q¹ is O. In certain embodiments, Q¹ is S. In certainembodiments, wherein when z is one, then R^(36z) and R^(37z) are nothalo.

In certain embodiments, R⁸a is

wherein z is an integer from 0 to 4,

R³⁵z is H or C₁-C₃alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N.

In other embodiments, R^(8a) is

for example

In some embodiments, R³⁵Z is H. In certain embodiments, each R^(36z) andR^(37z) are H. In certain embodiments, R^(38z) is H. In otherembodiments, R^(38z) is alkyl, for example C₁alkyl, C₂alkyl, or C₃alkyl.In other embodiments, R^(38z) is —C(═NH)NR³⁹R⁴⁰, for example —C(═NH)NH₂.In certain embodiments, R^(35z) and R^(38z), together with the atoms towhich they are attached, form a heterocycloalkyl group comprising atleast one N.

In some embodiments, z is an integer from 0 to 4, from 0 to 3, from 0 to2, from 1 to 4, from 2 to 4, or from 1 to 3. In certain embodiments, zis 0, or z is 1, or z is 2, or z is 3, or z is 4.

In some embodiments, R^(8a) is:

For example, R^(8a) may be:

In some embodiments, R^(38z) is H. For example, R⁸ may be:

In some embodiments, R^(8a) may be:

In some embodiments, R^(8a) may be:

In certain embodiments, R^(8a) is:

In certain embodiments, R^(8a) is:

In certain embodiments, R^(8a) is:

In other embodiments, at least one R^(36z) or R^(37z) is halogen. Forexample, in certain embodiments, R^(8a) is:

wherein each R^(36z) and R^(37z) is independently halogen, for examplefluoro.

In certain embodiments, at least one R^(36z) or R^(37z) is halogen, andR^(38z) is H. For example, R^(8a) may be:

wherein each R^(36z) and R^(37z) are independently halogen, for examplefluoro.

In other embodiments, at least one R^(36z) or R^(37z) is halogen. Forexample, in certain embodiments, R^(8a) is:

wherein each R^(36z) and R^(37z) is independently halogen, for examplefluoro.

In certain embodiments, at least one R^(36z) or R^(37z) is halogen, andR^(38z) is H. For example, R⁸ may be:

wherein each R^(36z) and R^(37z) are independently halogen, for examplefluoro.

In other embodiments, R^(8a) is

wherein at least one R^(36z) or R^(37z) is hydroxyl.

In other embodiments, R^(8a) is

wherein at least one R^(36z) or R^(37z) is hydroxyl.

In some embodiments, R^(38z) is C(═NH)NR^(39z)R^(40z), and R⁸ is:

In some embodiments, R^(39z) and R^(40z) are both H. In otherembodiments, R^(39z) and R^(40z) are both C₁-C₃alkyl. In still otherembodiments, one of R^(39z) and R^(40z) is H and the other isC₁-C₃alkyl.

R^(38z) may be —C(═NH)NH₂. Thus, in certain embodiments, R^(8a) is:

In certain embodiments, R^(36z) and one R^(37z), together with the atomsto which they are attached, form a carbocylic ring having from 3 to 6ring atoms.

In certain embodiments, R^(8b) is H. In certain embodiments, R^(8b) isC₁-C₃alkyl.

Synthesis of Compound AB-2

In some embodiments, the protecting groups of compound AB-1 are removedto yield compound AB-2, as described in Scheme 9. In some embodiments,the protecting groups of compound AB-1′ are removed to yield compoundAB-2′, as described in Scheme 9a. Scheme 9b is Scheme 9a, wherein N^(1s)is —NR^(8a)R^(8b).

With reference to Schemes 9, 9a, and 9b, the process further comprisesafter step (a):

(b) if amino protecting groups and hydroxyl protecting groups arepresent, remove the amino protecting groups and hydroxyl protectinggroups to yield a compound of formula AB-2, or a salt, solvate,enantiomer, or diastereomer thereof.

Reference to compounds AB-1 and AB-2 herein are meant to encompasscompounds AB-1′, AB-1″, AB-2′ and AB-2″. In certain embodiments, theprocess comprises removing the amino protecting groups Pg^(1e) andPg^(1f) or converting N₃ to —NH₂ and removing the hydroxyl protectinggroup Pg^(2e) to yield a compound of formula AB-2, or a salt, solvate,enantiomer, or diastereomer thereof.

Conditions for removing protecting group can be found in “ProtectiveGroups in Organic Synthesis, 4th Ed”, Wiley-Interscience, Inc., 2007(Theodora W. Greene, Peter G. M. Wuts); “Protecting Groups 3rd Ed.”Thieme, 2004 (P. J. Kocienski). In certain embodiments, hydrolysis orhydrogenation can be used to remove the protecting groups.

Embodiments of Compound AB

In certain embodiments, the stereochemistry of compound AB-1, AB-2, andAB-3, or a salt, solvate, enantiomer, or diastereomer thereof, is asindicated in formula (AB′):

In certain embodiments, the stereochemistry of compound AB-1, AB-2, andAB-3, or a salt, solvate, enantiomer, or diastereomer thereof, is asindicated in formula (AB^(S2)), wherein

indicates a point of attachment to a hydrogen or a moiety:

In certain embodiments, the stereochemistry of compound AB-1′, AB-2′,and AB-3′, or a salt, solvate, enantiomer, or diastereomer thereof, isas indicated in formula (AB″):

In certain embodiments, the stereochemistry of compound AB-1′, AB-2′,and AB-3′, or a salt, solvate, enantiomer, or diastereomer thereof, isas indicated in formula (AB^(s4)), wherein

indicates a point of attachment to a hydrogen or a moiety:

In certain embodiments, m is one. In certain embodiments, n is one. Incertain embodiments, m is one and n is one.

In certain embodiments, o is one. In certain embodiments, p is one. Incertain embodiments, o is one and p is one.

Preparation of ABC

The present disclosure includes processes, methods, reagents, andintermediates for the synthesis of compound ABC, as shown in Schemes 10,10a, and 10b. In compound AB-1 and AB-1′, the hydroxyl protecting groupis selectively removed to form a hydroxyl group, which is suitable ofreacting with a reactant or a glycosyl donor, to form an interglycosidiclinkage. In compound C-1, LVG⁴ is a leaving group suitable of reactingwith a reactant or a glycosyl acceptor, to form an interglycosidiclinkage.

The present disclosure provides a process for preparing a process forpreparing a compound of formula ABC-1, comprising the following stepsafter the preparation of compound AB-1, shown above:

(b) selectively deprotecting the compound of formula AB-1 by removingthe Pg^(2e) moiety to yield a compound of formula AB-3:

or a salt, solvate, enantiomer, or diastereomer thereof;

(c) contacting the compound of formula AB-3 with a compound of formulaC-1,

or a salt, solvate, enantiomer, or diastereomer thereof, wherein

R^(7a), R^(7b), and R^(7c) are, independently, H, NH₂, OH, —OR⁷¹ or—OPg^(2r);

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen,and substituted heteroaryl;

wherein Pg^(2r) is a protecting group for hydroxyl group;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

Pg^(2f) is a hydroxyl protecting group;

LVG⁴ is a leaving group;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3;

to yield a compound of formula ABC-1, or a salt, solvate, enantiomer, ordiastereomer thereof,

A process for the preparation of compound ABC-1′ is illustrated inSchemes 10a and 10b below and is discussed in greater detail herein.Scheme 10b is Scheme 10a, wherein N^(1s) is —NR^(8a)R^(8b).

With reference to Schemes 10a, the present disclosure provides a processfor preparing a process for preparing a compound of formula ABC-1′. Thepresent disclosure provides a process for preparing a process forpreparing a compound of formula ABC-1′, comprising the following stepsafter the preparation of compound AB-1′, shown above:

(b) selectively deprotecting the compound of formula AB-1′ by removingthe Pg^(2e) moiety to yield a compound of formula AB-3′:

or a salt, solvate, enantiomer, or diastereomer thereof;

(c) contacting the compound of formula AB-3 with a compound of formulaC-1,

or a salt, solvate, enantiomer, or diastereomer thereof, wherein

R^(7a), R^(7b), and R^(7c) are, independently, H, NH₂, OH, —OR⁷¹ or—OPg^(2r);

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen,and substituted heteroaryl;

wherein Pg^(2r) is a protecting group for hydroxyl group;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

Pg^(2f) is a hydroxyl protecting group;

LVG⁴ is a leaving group;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3;

to yield a compound of formula ABC-1′, or a salt, solvate, enantiomer,or diastereomer thereof,

Synthesis of Compound ABC-1

Reference to compounds AB-1 to AB-3 are meant to encompass compoundsAB-1′ to AB-3′ and AB-1″ to AB-3″. With reference to Schemes 10, 10a,and 10b, a selective removal of the Pg^(2e) protecting group of compoundAB-1 to yield compound AB-3, which has a hydroxyl group resulting fromthe selective removal of the Pg^(2e) protecting group. Selective removalof Pg^(2e) protecting group can be performed by hydrolysis. For example,removal of protecting group can be performed by hydrolysis underconditions such as base (for example, NaOH, KOH, Et₃N) or acid mediated(for example, HCl, TfOH, p-TSA) in aqueous media optionally includingoraganic solvents (for example, MeOH, Et₂O, DMF) at temperatures between0° C. and the reflux point of the solvent.

With continued reference to Schemes 10, 10a, and 10b, compound AB-3 iscontacted with compound C-1 to yield compound ABC-1. The reaction isperformed under to conditions to allow for chemical glycosylation withcoupling of a glycosyl donor and a glycosyl acceptor. In Scheme 10, 10a,and 10b, a glycosyl donor (LVW on compound C-1) and a glycosyl acceptor(—OH on compound AB-3) are coupled. In certain embodiments, LVG⁴ isselected from the group consisting of OH, halides, thioalkyl groups,thioaryl groups, imidates, acetate, phosphate, and O-pentenyl groups. Incertain embodiments, LVG⁴ is halo, OMs, OTs, OH, a thioalkyl, athioaryl, an imidate, an acetate, a phosphate, or an O-pentenyl group.

In certain embodiments, a suitable activating reagent is provided toassist the chemical glycosylation reaction. In certain embodiments, BF3is used as an activating agent. In certain embodiments, standardglycosyl formation conditions include use of an activating agent, suchas BF₃.Et₂O or AlMe₃ in solvents such as MeOH or THF at temperaturesbetween 0° C. and room temperature.

Synthesis of Compound ABC-2

In some embodiments, the protecting groups of compound ABC-1 are removedto yield a compound ABC-2, as described in Scheme 11. In someembodiments, the protecting groups of compound ABC-1′ are removed toyield a compound ABC-2′, as described in Scheme 11a. Scheme 11b isScheme 11a, wherein N^(1s) is —NR^(8a)R^(8b).

With reference to Schemes 11, 11a, and 11b, the process furthercomprises after step (c):

(d) if amino protecting groups and hydroxyl protecting groups arepresent, remove the amino protecting groups and hydroxyl protectinggroups to yield a compound of formula ABC-2, or a salt, solvate,enantiomer, or diastereomer thereof.

Reference to compounds ABC-1 and ABC-2 herein are meant to encompasscompounds ABC-1′, ABC-1″, ABC-2′ and ABC-2″. In certain embodiments, theprocess comprises removing the amino protecting groups Pg^(1e) andPg^(1f) or converting N₃ to —NH₂ and removing hydroxyl protecting groupPg^(2f) to yield a compound of formula ABC-2, or a salt, solvate,enantiomer, or diastereomer thereof.

Conditions for removing protecting group can be found in “ProtectiveGroups in Organic Synthesis, 4th Ed”, Wiley-Interscience, Inc., 2007(Theodora W. Greene, Peter G. M. Wuts); “Protecting Groups 3rd Ed.”Thieme, 2004 (P. J. Kocienski). In certain embodiments, hydrolysis orhydrogenation can be used to remove the protecting groups.

Additional Preparation of Compound ABC

Compound ABC can also be prepared with the use of a catalyst, such as anenzyme, for example, as described in Examples 43 and 44.

Embodiments of Compound ABC

In certain embodiments, the stereochemistry in the ring of formulaeABC-1 and ABC-2, is as indicated in formula (ABC'),

In certain embodiments, the stereochemistry of compound ABC-1′, ABC-2′,and ABC-3′, or a salt, solvate, enantiomer, or diastereomer thereof, isas indicated in formula (ABC″):

In certain embodiments, m is one. In certain embodiments, n is one. Incertain embodiments, m is one and n is one.

In certain embodiments, o is one. In certain embodiments, p is one. Incertain embodiments, o is one and p is one.

In certain embodiments, q is one. In certain embodiments, q is zero. Incertain embodiments, r is one. In certain embodiments, r is zero. Incertain embodiments, q is one and r is zero. In certain embodiments, qis zero and r is one.

Preparation of ABCD

The present disclosure includes processes, methods, reagents, andintermediates for the synthesis of compound ABCD-1, as shown in Schemes12, 12a, and 12b In compound AB-1, the hydroxyl protecting group isselectively removed to expose a hydroxyl group, which is suitable ofreacting with a reactant or a glycosyl donor, to form an interglycosidiclinkage. In compound CD-1, LVG⁵ is a leaving group suitable of reactingwith a reactant or a glycosyl acceptor, to form an interglycosidiclinkage.

The present disclosure provides a process for preparing a process forpreparing a compound of formula ABCD-1, comprising the following stepsafter the preparation of compound AB-1, shown above:

(b) selectively deprotecting the compound of formula AB-1 by removingthe Pg^(2e) moiety to yield a compound of formula AB-3:

or a salt, solvate, enantiomer, or diastereomer thereof;

(c) contacting the compound of formula AB-3 with a compound of formulaCD-1,

or a salt, solvate, enantiomer, or diastereomer thereof, wherein

R^(7a), R^(7b), and R^(7c) are, independently, H, NH₂, OH, —OR⁷¹ or—OPg^(2r);

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen,and substituted heteroaryl;

wherein Pg^(2r) is a protecting group for hydroxyl group;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

LVG⁵ is a leaving group;

N^(1g) is —NHPg^(1g) or N₃, wherein Pg^(1g) is an amino protectinggroup;

N^(1h)is —NHPg^(1h) or N₃, wherein Pg^(1h) is an amino protecting group;

Pg^(2g) is a hydroxyl protecting group;

Pg^(2h) is a hydroxyl protecting group;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3;

to yield a compound of formula ABCD-1, or a salt, solvate, enantiomer,or diastereomer thereof,

A process for the preparation of compound ABCD-1′ is illustrated inScheme 12a below and is discussed in greater detail herein. Scheme 12bis Scheme 12a, wherein N^(1s) is —NR^(8a)R^(8b).

With reference to Scheme 12a, in compound AB-1′, the hydroxyl protectinggroup is selectively removed to expose a hydroxyl group, which issuitable of reacting with a reactant or a glycosyl donor, to form aninterglycosidic linkage. In compound CD-1, LVG⁵ is a leaving groupsuitable of reacting with a reactant or a glycosyl acceptor, to form aninterglycosidic linkage.

The present disclosure provides a process for preparing a process forpreparing a compound of formula ABCD-1′, comprising the following stepsafter the preparation of compound AB-1′, shown above:

(b) selectively deprotecting the compound of formula AB-1′ by removingthe Pg^(2e) moiety to yield a compound of formula AB-3′:

or a salt, solvate, enantiomer, or diastereomer thereof;

(c) contacting the compound of formula AB-3 with a compound of formulaCD-1,

or a salt, solvate, enantiomer, or diastereomer thereof, wherein

R^(7a), R^(7b), and R^(7c) are, independently, H, NH₂, OH, —OR⁷¹ or—OPg^(2r);

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen,and substituted heteroaryl;

wherein Pg^(2r) is a protecting group for hydroxyl group;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

LVG⁵ is a leaving group;

N^(1g) is —NHPg^(1g) or N₃, wherein Pg^(1g) is an amino protectinggroup;

N^(1h) is —NHPg^(1h) or N₃, wherein Pg^(1h) is an amino protectinggroup;

Pg^(2g) is a hydroxyl protecting group;

Pg^(2h) is a hydroxyl protecting group;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3;

to yield a compound of formula ABCD-1′, or a salt, solvate, enantiomer,or diastereomer thereof,

Synthesis of Compound ABCD-1

Reference to compounds AB-1 to AB-3 are meant to encompass compoundsAB-1′ to AB-3′ and AB-1″ to AB-3″. With reference to Schemes 12, 12a,and 12b, a selective removal of the Pg^(2e) protecting group of compoundAB-1 to yield compound AB-3, which has a hydroxyl group resulting fromthe selective removal of the Pg^(2e) protecting group. Selective removalof Pg^(2e) protecting group can be performed by hydrolysis. For example,removal of protecting group can be performed by hydrolysis underconditions such as base (for example, NaOH, KOH, Et₃N) or acid mediated(for example, HCl, TfOH, p-TSA) in aqueous media optionally includingoraganic solvents (for example, MeOH, Et₂O, DMF) at temperatures between0° C. and the reflux point of the solvent.

With continued reference to Schemes 12, 12a, and 12b, compound AB-3 iscontacted with compound CD-1 to yield compound ABCD-1. The reaction isperformed under to conditions to allow for chemical glycosylation withcoupling of a glycosyl donor and a glycosyl acceptor. In Scheme 12, 12a,and 12b, a glycosyl donor (LVG⁵ on compound CD-1) and a glycosylacceptor (—OH on compound AB-3) are coupled. In certain embodiments,LVG⁵ is selected from the group consisting of OH, halides, thioalkylgroups, thioaryl groups, imidates, acetate, phosphate, and O-pentenylgroups. In certain embodiments, LVG⁵ is halo, OMs, OTs, OH, a thioalkyl,a thioaryl, an imidate, an acetate, a phosphate, or an O-pentenyl group.

In certain embodiments, a suitable activating reagent is provided toassist the chemical glycosylation reaction. In certain embodiments, BF3is used as an activating agent. In certain embodiments, standardglycosyl formation conditions include use of an activating agent, suchas BF₃.Et₂O or AlMe₃ in solvents such as MeOH or THF at temperaturesbetween 0° C. and room temperature.

Synthesis of Compound ABCD-2

In some embodiments, the protecting groups of compound ABCD-1 areremoved to yield a compound ABCD-2, as described in Scheme 13. In someembodiments, the protecting groups of compound ABCD-1′ are removed toyield a compound ABCD-2′, as described in Scheme 13a. Scheme 13b isScheme 13a, wherein N^(1s) is —NR^(8a)R^(8b).

With reference to Schemes 13, 13a, and 13b, the process furthercomprises after step (c):

(d) if amino protecting groups and hydroxyl protecting groups arepresent, remove the amino protecting groups and hydroxyl protectinggroups to yield a compound of formula ABCD-2, or a salt, solvate,enantiomer, or diastereomer thereof.

Reference to compounds ABCD-1 and ABCD-2 herein are meant to encompasscompounds ABCD-1′, ABCD-1″, ABCD-2′ and ABCD-2″. In certain embodiments,the process comprises removing the amino protecting groups Pg^(1e),Pg^(1f), Pg^(1g), and Pg^(1h) or converting N₃ to —NH₂ and removing andhydroxyl protecting groups Pg^(2g) and Pg^(2h) to yield a compound offormula ABCD-2, or a salt, solvate, enantiomer, or diastereomer thereof.

Conditions for removing protecting group can be found in “ProtectiveGroups in Organic Synthesis, 4th Ed”, Wiley-Interscience, Inc., 2007(Theodora W. Greene, Peter G. M. Wuts); “Protecting Groups 3rd Ed.”Thieme, 2004 (P. J. Kocienski). In certain embodiments, hydrolysis orhydrogenation can be used to remove the protecting groups.

Additional Preparation of Compound ABCD

Compound ABCD can also be prepared with the use of a catalyst, such asan enzyme, for example, as described in Examples 43 and 44

Embodiments of Compound ABCD

In certain embodiments, the stereochemistry in the ABCD ring areindicated as in formula (ABCD'):

In certain embodiments, the stereochemistry in the ABCD ring areindicated as in formula (ABCD″):

In certain embodiments, m is one. In certain embodiments, n is one. Incertain embodiments, m is one and n is one.

In certain embodiments, o is one. In certain embodiments, p is one. Incertain embodiments, o is one and p is one.

In certain embodiments, q is one. In certain embodiments, q is zero. Incertain embodiments, r is one. In certain embodiments, r is zero. Incertain embodiments, q is one and r is zero. In certain embodiments, qis zero and r is one.

Compounds of Formulae A, B, AB, ABC, ABCD Compounds of formula A

The present disclosure provides a compound of formula A-10:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X³ is selected from the group consisting of H, NH₂, N₃, protected aminogroup, OH, —OPg^(2i), and halogen; wherein Pg^(2i) is a hydroxylprotecting group;

LVG⁶ is a leaving group;

N^(1i) is —NHPg^(1i), —NH₂, or N₃, wherein each Pg^(1i) is independentlyan amino protecting group;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3.

The present disclosure provides a compound of formula A-10′:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(1a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H, alkyl,amino protecting group, or hydroxyl protecting group; wherein the C₁-C₆alkyl or alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of aryl, halogen, —OR³⁰,—NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X³ is selected from the group consisting of H, NH₂, N₃, protected aminogroup, OH, —OPg^(2i), and halogen; wherein Pg^(2i) is a hydroxylprotecting group;

LVG⁶ is a leaving group;

N^(1i) is —OH, protected hydroxyl group, —NHPg^(1i), N(Pg^(1i))₂, —NH₂,or N₃, wherein each Pg^(1i) is independently an amino protecting group;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3.

Compounds of formula B

The present disclosure provides a compound of formula B-13:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl; wherein thealkyl is unsubstituted or substituted with one or more substituentsselected from the group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl,substituted aryl, heteroaryl, halogen, and substituted heteroaryl;

R^(5a) is H, —CN, CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j); wherein Pg^(2j) is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R¹¹ is H, alkyl, —COCH₃, or a hydroxyl protecting group;

N^(1j) is —NHPg^(1j), —NH₂, or N₃, wherein Pg^(1j) is an aminoprotecting group;

Pg^(2s) is H or hydroxyl protecting group;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3.

The present disclosure provides a compound of formula (B-13′)

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(4aa) and R^(4bb) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H, alkyl, —CONH₂, or—COCH₃; wherein the alkyl is unsubstituted or substituted with one ormore substituents selected from the group consisting of —CONH₂, —OH,—NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen, andsubstituted heteroaryl;

R^(5aa) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —OC(O)CH₃, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j); wherein Pg^(2j) is a hydroxyl protecting group;

N^(1s) is N₃ or —NR^(8a)R^(8b);

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR ^(39z)R^(40z), wherein R^(39z) andR^(49z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(8b) is H or C₁-C₃alkyl;

R¹¹ is H, alkyl, —COCH₃, or a hydroxyl protecting group;

N^(1j) is —NHPg^(1j), —NH₂, or N₃, wherein Pg^(1j) is an aminoprotecting group;

Pg^(2s) is H or hydroxyl protecting group;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3.

Compounds of formula AB

The present disclosure provides a compound of formula AB-4:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵ and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X⁴ is selected from the group consisting of H, NH₂, N₃, protected aminogroup, OH, —OPg^(2k), and halogen; wherein Pg^(2k) is a hydroxylprotecting group;

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl; wherein thealkyl is unsubstituted or substituted with one or more substituentsselected from the group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl,substituted aryl, heteroaryl, halogen, and substituted heteroaryl;

R^(5a) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j);

wherein Pg^(2j) is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(49z), wherein R^(39z) andR^(49z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R¹¹ is H, alkyl, —COCH₃, or a hydroxyl protecting group;

N^(1m) is —NHPg^(1m), —NH₂, or N₃, wherein Pg^(1m) is an aminoprotecting group;

N^(1n) is —NHPg^(1n), —NH₂, or N₃, wherein Pg^(1n) is an aminoprotecting group;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3.

The present disclosure provides a compound of formula AB-4′:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b)R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H, alkyl,amino protecting group, or hydroxyl protecting group; wherein the C₁-C₆alkyl or alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of aryl, halogen, —OR³⁰,—NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X⁴ is selected from the group consisting of H, NH₂, N₃, protected aminogroup, OH, —OPg^(2k), and halogen; wherein Pg^(2k) is a hydroxylprotecting group;

R^(4aa) and R^(4bb) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H, alkyl, —CONH₂, or—COCH₃; wherein the alkyl is unsubstituted or substituted with one ormore substituents selected from the group consisting of —CONH₂, —OH,—NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen, andsubstituted heteroaryl;

R^(5aa) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —OC(O)CH₃, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j); wherein Pg^(2j) is a hydroxyl protecting group;

N^(1s) is N₃ or —NR^(8a)R^(8b);

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(8b) is H or C₁-C₃alkyl;

R¹¹ is H, alkyl, —COCH₃, or a hydroxyl protecting group;

N^(1m) is —OH, protected hydroxyl group, —NHPg^(1m), N(Pg^(1m))₂, —NH₂,or N₃, wherein each Pg^(1m) is independently an amino protecting group;

N^(1n) is —NHPg^(1n), —NH₂, or N₃, wherein Pg^(1n) is an aminoprotecting group;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3.

The present disclosure provides a compound of formula AB-5:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵,and —OR¹⁶;

R^(2a), R^(2b), R^(3a) ad R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl;

wherein the alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, halogen, and substitutedheteroaryl;

R^(5a) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2m); wherein Pg^(2m) is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

N^(1e) is —NHPg^(1e) or N₃, wherein Pg^(1e) is an amino protectinggroup;

N^(1f) is —NHPg^(1f) or N₃, wherein Pg^(1f) is an amino protectinggroup;

Pg^(2e) is a hydroxyl protecting group;

X is —NH₂, —N₃, protected amino group, —OH, or protected hydroxyl group;

wherein at least one of N^(1e) and N^(1f) is not NH₂ or wherein PG^(2e)is not H or wherein X is not —OH or —NH₂;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3.

The present disclosure provides a compound of formula AB-5′:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H, alkyl,amino protecting group, or hydroxyl protecting group; wherein the C₁-C₆alkyl or alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of aryl, halogen, —OR³⁰,—NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(4aa) and R^(4bb) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H, alkyl, —CONH₂, or—COCH₃; wherein the alkyl is unsubstituted or substituted with one ormore substituents selected from the group consisting of —CONH₂, —OH,—NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen, andsubstituted heteroaryl;

R^(5aa) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —OC(O)CH₃, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2m); wherein Pg^(2m) is a hydroxyl protecting group;

N^(1s) is N₃ or —NR^(8a)R^(8b)l

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(8b) is H or C₁-C₃alkyl;

N^(1m) is —OH, protected hydroxyl group, —NHPg^(1m), N(Pg^(1m))₂, —NH₂,or N₃, wherein each Pg^(1m) is independently an amino protecting group;

N^(1n) is —NHPg^(1n), —NH₂, or N₃, wherein Pg^(1n) is an aminoprotecting group;

Pg^(2e) is H or a hydroxyl protecting group;

X⁴ is selected from the group consisting of H, NH₂, N₃, protected aminogroup, OH, —OPg^(2k), and halogen; wherein Pg^(2k) is a hydroxylprotecting group;

wherein at least one of N^(1m) and N^(1n) is not NH₂ or wherein PG^(2e)is not H or wherein X⁴ is not —OH or —NH₂;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3.

The present disclosure provides a compound of formula AB-1:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸—R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl;

wherein the alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, halogen, and substitutedheteroaryl;

R^(5a) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2m); wherein Pg^(2m) is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

N^(1e) is —NHPg^(1e) or N₃, wherein Pg^(1e) is an amino protectinggroup;

N^(1f) is —NHPg^(1f) or N₃, wherein Pg^(1f) is an amino protectinggroup;

Pg^(2e) is a hydroxyl protecting group;

X is NH₂, —N₃, protected amino group, —OH, or protected hydroxyl group;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3.

The present disclosure provides a compound of formula AB-1′:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵ and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵,and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H, alkyl,amino protecting group, or hydroxyl protecting group; wherein the C₁-C₆alkyl or alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of aryl, halogen, —OR³⁰,—NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(1a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(4aa) and R^(4bb) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H, alkyl, —CONH₂, or—COCH₃; wherein the alkyl is unsubstituted or substituted with one ormore substituents selected from the group consisting of —CONH₂, —OH,—NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen, andsubstituted heteroaryl;

R^(5aa) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —OC(O)CH₃, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2m); wherein Pg^(2m) is a hydroxyl protecting group;

N^(1s) is N₃ or −NR^(8a)R^(8b);

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

-   -   wherein    -   Q¹ is NH, O, or S;    -   z is an integer from 0 to 4,    -   R^(35z) is H or C₁-C₃ alkyl;    -   each R^(36z) and R^(37z) is independently selected from the        group consisting of H, alkyl, halogen, and —OH, and    -   R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z)        and R^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(8b) is H or C₁-C₃alkyl;

N^(1e) is —OH, protected hydroxyl group, —NHPg^(1e), —N(Pg^(1e))₂, —NH₂,or N₃, wherein each Pg^(1e) is independently an amino protecting group;

N^(1f) is —NHPg^(1f) or N₃, wherein Pg^(1f) is an amino protectinggroup;

Pg^(2e) is a hydroxyl protecting group;

X⁴ is selected from the group consisting of H, NH₂, N₃, protected aminogroup, OH, —OPg^(2k), and halogen; wherein Pg^(2k) is a hydroxylprotecting group;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3.

The present disclosure provides a compound of formula AB-2:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl;

wherein the alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, halogen, and substitutedheteroaryl;

R^(5a) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2m); wherein Pg^(2m) is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(49z), wherein R^(39z) andR^(49z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

X is —NH₂ or —OH;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3.

The present disclosure provides a compound of formula AB-2″:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, —NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H, alkyl,amino protecting group, or hydroxyl protecting group; wherein the C₁-C₆alkyl or alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of aryl, halogen, —OR³⁹,—NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(4aa) and R^(4bb) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H, alkyl, —CONH₂, or—COCH₃; wherein the alkyl is unsubstituted or substituted with one ormore substituents selected from the group consisting of —CONH₂, —OH,—NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen, andsubstituted heteroaryl;

R^(5aa) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —OC(O)CH₃, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2m); wherein Pg^(2m) is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

N^(1e′) is —OH or —NH₂;

R^(8b) is H or C₁-C₃alkyl;

X^(4′) is selected from the group consisting of H, NH₂, OH, and halogen;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3.

Compounds of Formula ABC

The present disclosure provides a compound of formula ABC-3:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X⁵ is selected from the group consisting of H, NH₂, N₃, protected aminogroup, OH, —OPg²¹, and halogen; wherein Pg²¹ is a hydroxyl protectinggroup;

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl; wherein thealkyl is unsubstituted or substituted with one or more substituentsselected from the group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl,substituted aryl, heteroaryl, halogen, and substituted heteroaryl;

R^(5a) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —NH₂, —CN, CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j);

wherein Pg^(2j) is a hydroxyl protecting group;

R^(7a), R^(7b), and R^(7c) are, independently, H, OH, —OR⁷¹ or —OPg²;

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl;

wherein Pg² is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

N^(1o) is —NHPg^(1o), —NH₂, or N₃, wherein Pg^(1o) is an aminoprotecting group;

N^(1p) is —NHPg^(1p), —NH₂, or N₃, wherein Pg^(1p) is an aminoprotecting group;

Pg^(2f) is a hydroxyl protecting group or H;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3.

The present disclosure provides a compound of formula ABC-3′:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H, alkyl,amino protecting group, or hydroxyl protecting group; wherein the C₁-C₆alkyl or alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of aryl, halogen, —OR³⁰,—NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X⁵ is selected from the group consisting of H, NH₂, N₃, protected aminogroup, OH, —OPg²¹, and halogen; wherein Pg²¹ is a hydroxyl protectinggroup;

R^(4aa) and R^(4bb) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H, alkyl, —CONH₂, or—COCH₃; wherein the alkyl is unsubstituted or substituted with one ormore substituents selected from the group consisting of —CONH₂, —OH,—NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen, andsubstituted heteroaryl;

R^(5aa) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —OC(O)CH₃, —NH₂, —CN, CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j);

wherein Pg^(2j) is a hydroxyl protecting group;

R^(7a), R^(7b), and R^(7c) are, independently, H, OH, —OR⁷¹ or —OPg²;

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl;

wherein Pg² is a hydroxyl protecting group;

N^(1s) is N₃ or —NR^(8a)R^(8b);

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(49z), wherein R^(39z) andR^(49z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(8b) is H or C₁-C₃alkyl;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

N^(1o) is —OH, protected hydroxyl group, —NHPg^(1o), N(Pg^(1o))₂, —NH₂,or N₃, wherein each Pg^(1o) is independently an amino protecting group;

N^(1p) is —NHPg^(1p), —NH₂, or N₃, wherein Pg^(1p) is an aminoprotecting group;

Pg^(2f) is a hydroxyl protecting group or H;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3.

The present disclosure provides a compound of formula ABC-4:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R^(15,) and R¹⁶ is independently H or alkyl;or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X is —NH₂, —N₃, protected amino group, —OH, or protected hydroxyl group;

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl; wherein thealkyl is unsubstituted or substituted with one or more substituentsselected from the group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl,substituted aryl, heteroaryl, halogen, and substituted heteroaryl;

R^(5a) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j);

wherein Pg^(2j) is a hydroxyl protecting group;

R^(7a), R^(7b), and R^(7c) are, independently, H, OH, —OR⁷¹ or —OPg²;

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl;

wherein Pg² is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40a) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

N^(1o) is —NHPg^(1o), —NH₂, or N₃, wherein Pg^(1o) is an aminoprotecting group;

N^(1p) is —NHPg^(1p), —NH₂, or N₃, wherein Pg^(1p) is an aminoprotecting group;

Pg^(2f) is a hydroxyl protecting group or H;

wherein at least one of N^(1e) and N^(1f) is not NH₂ or wherein Pg^(2f)is not H or wherein X is not OH or —NH₂;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3.

The present disclosure provides a compound of formula ABC-4′:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H, alkyl,amino protecting group, or hydroxyl protecting group; wherein the C₁-C₆alkyl or alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of aryl, halogen, —OR³⁰,—NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X⁵ is selected from the group consisting of H, NH₂, N₃, protected aminogroup, OH, —OPg²¹, and halogen; wherein Pg²¹ is a hydroxyl protectinggroup;

R^(4aa) and R^(4bb) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H, alkyl, —CONH₂, or—COCH₃; wherein the alkyl is unsubstituted or substituted with one ormore substituents selected from the group consisting of —CONH₂, —OH,—NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen, andsubstituted heteroaryl;

R^(5aa) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —OC(O)CH₃, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j);

wherein Pg^(2j) is a hydroxyl protecting group;

R^(7a), R^(7b), and R^(7c) are, independently, H, OH, —OR⁷¹ or —OPg²;

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl;

wherein Pg² is a hydroxyl protecting group;

N^(1s) is N₃ or —NR^(8a)R^(8b);

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(8b) is H or C₁-C₃alkyl;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

N^(1o) is —OH, protected hydroxyl group, —NHPg^(1o), N(Pg^(1o))₂, —NH₂,or N₃, wherein each Pg^(1o) is independently an amino protecting group;

N^(1p) is —NHPg^(1p), —NH₂, or N₃, wherein Pg^(1p) is an aminoprotecting group;

Pg^(2f) is a hydroxyl protecting group or H;

wherein at least one of N^(1o) and N^(1p) is not NH₂ or wherein Pg^(2f)is not H or wherein X⁵ is not —OH or —NH₂;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3.

The present disclosure provides a compound of formula ABC-1:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸, R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X is —NH₂, —N₃, protected amino group, —OH, or protected hydroxyl group;

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl; wherein thealkyl is unsubstituted or substituted with one or more substituentsselected from the group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl,substituted aryl, heteroaryl, halogen, and substituted heteroaryl;

R^(5a) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j);

wherein Pg^(2j) is a hydroxyl protecting group;

R^(7a), R^(7b), and R^(7c) are, independently, H, OH, —OR⁷¹ or —OPg²;

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl;

wherein Pg² is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR ^(39z)R^(40z), wherein R^(39z) andR^(40z) _(are) independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

N^(1e) is —NHPg^(1e) or N₃, where in Pg^(1e) is an amino protectinggroup;

N^(1f) is —NHPg^(1f) or N₃, wherein Pg^(1f) is an amino protectinggroup;

Pg^(2f) is a hydroxyl protecting group;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3.

The present disclosure provides a compound of formula ABC-1′:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴T¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H, alkyl,amino protecting group, or hydroxyl protecting group; wherein the C₁-C₆alkyl or alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of aryl, halogen, —OR³⁰,—NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X⁵ is selected from the group consisting of H, NH₂, N₃, protected aminogroup, OH, —OPg²¹, and halogen; wherein Pg²¹ is a hydroxyl protectinggroup;

R^(4aa) and R^(4bb) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H, alkyl, —CONH₂, or—COCH₃; wherein the alkyl is unsubstituted or substituted with one ormore substituents selected from the group consisting of —CONH₂, —OH,—NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen, andsubstituted heteroaryl;

R^(5aa) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —OC(O)CH₃, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j);

wherein Pg^(2j) is a hydroxyl protecting group;

R^(7a), R^(7b), and R^(7c) are, independently, H, OH, —OR⁷¹ or —OPg²;

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl;

wherein Pg² is a hydroxyl protecting group;

N^(1s) is N₃ or —NR^(8a)R^(8b),

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(49z), wherein R^(39z) andR^(49z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(8b) is H or C₁-C₃alkyl;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

N^(1e) is —OH, protected hydroxyl group, −NHPg^(1e), N(Pg^(1e))₂, —NH₂,or N₃, wherein each Pg^(1e) is independently an amino protecting group;

N^(1f) is —NHPg^(1f) or N₃, wherein Pg^(1f) is an amino protectinggroup;

Pg^(2f) is a hydroxyl protecting group;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3.

The present disclosure provides a compound of formula ABC-2:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X is —NH₂ or —OH;

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl; wherein thealkyl is unsubstituted or substituted with one or more substituentsselected from the group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl,substituted aryl, heteroaryl, halogen, and substituted heteroaryl;

R^(5a) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j); wherein Pg^(2j) is a hydroxyl protecting group;

R^(7a), R^(7b), and R^(7c) are, independently, H, OH, —OR⁷¹ or —OPg²;

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl;

wherein Pg² is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3.

The present disclosure provides a compound of formula ABC-2″:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H, alkyl,amino protecting group, or hydroxyl protecting group; wherein the C₁-C₆alkyl or alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of aryl, halogen, —OR³⁰,—NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X^(5′) is selected from the group consisting of H, NH₂, OH, and halogen;

R^(4aa) and R^(4bb) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H, alkyl, —CONH₂, or—COCH₃; wherein the alkyl is unsubstituted or substituted with one ormore substituents selected from the group consisting of —CONH₂, —OH,—NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen, andsubstituted heteroaryl;

R^(5aa) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —OC(O)CH₃, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j); wherein Pg^(2j) is a hydroxyl protecting group;

R^(7a), R^(7b), and R^(7c) are, independently, H, OH, —OR⁷¹ or —OPg²;

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl;

wherein Pg² is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

N^(1e′) is —OH or —NH₂;

R^(8b) is H or C₁-C₃alkyl;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3.

Compounds of Formula ABCD

The present disclosure provides a compound of formula ABCD-3:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X⁶ is selected from the group consisting of H, NH₂, N₃, protected aminogroup, OH, —OPg^(2m), and halogen; wherein Pg^(2m) is a hydroxylprotecting group;

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl;

wherein the alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, halogen, and substitutedheteroaryl;

R^(5a) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j); wherein Pg^(2j) is a hydroxyl protecting group;

R^(7a), R^(7b), and R^(7c) are, independently, H, OH, —OR⁷¹ or —OPg²;

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl;

wherein Pg² is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

N^(1q) is —NHPg^(1q) or N₃, wherein Pg^(1q) is an amino protectinggroup;

N^(1r) is —NHPg^(1r) or N₃, wherein Pg^(1r) is an amino protectinggroup;

N^(1g) is —NHPg^(1g) or N₃, wherein Pg^(1g) is an amino protectinggroup;

N^(1h) is —NHPg^(1h) or N₃, wherein Pg^(1h) is an amino protectinggroup;

Pg^(2g) is a hydroxyl protecting group;

Pg^(2h) is a hydroxyl protecting group;

wherein at least one of N^(1q), N^(1r), N^(1g), N^(1h) is not NH₂ orwherein at least one of PG^(2g) or Pg^(2h) is not H or wherein X⁶ is not—OH or —NH₂;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3.

The present disclosure provides a compound of formula ABCD-3′:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H, alkyl,amino protecting group, or hydroxyl protecting group; wherein the C₁-C₆alkyl or alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of aryl, halogen, —OR³⁰,—NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X⁶ is selected from the group consisting of H, NH₂, N₃, protected aminogroup, OH, —OPg^(2m), and halogen; wherein Pg^(2m) is a hydroxylprotecting group;

R^(4aa) and R^(4bb) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H, alkyl, —CONH₂, or—COCH₃; wherein the alkyl is unsubstituted or substituted with one ormore substituents selected from the group consisting of —CONH₂, —OH,—NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen, andsubstituted heteroaryl;

R^(5aa) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —OC(O)CH₃, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j); wherein Pg^(2j) is a hydroxyl protecting group;

R^(7a), R^(7b), and R^(7c) are, independently, H, OH, —OR⁷¹ or —OPg²;

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl;

wherein Pg² is a hydroxyl protecting group;

N^(1s) is N₃ or —NR^(8a)R^(8b);

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(8b) is H or C₁-C₃alkyl;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

N^(1q) is —OH, protected hydroxyl group, —NHPg^(1q), N(Pg^(1q))₂, —NH₂,or N₃, wherein each Pg^(1i) is independently an amino protecting group;

N^(1r) is —NHPg^(1r) or N₃, wherein Pg^(1r) is an amino protectinggroup;

N^(1g) is —NHPg^(1g) or N₃, wherein Pg^(1g) is an amino protectinggroup;

N^(1h) is —NHPg^(1h) or N₃, wherein Pg^(1h) is an amino protectinggroup;

Pg^(2g) is a hydroxyl protecting group;

Pg^(2h) is a hydroxyl protecting group;

wherein at least one of N^(1q), N^(1r), N^(1g), N^(1h) is not NH₂ orwherein at least one of PG^(2g) or Pg^(2h) is not H or wherein X⁶ is not—OH or —NH₂;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3.

The present disclosure provides a compound of formula ABCD-4:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸ R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X⁶ is selected from the group consisting of H, NH₂, N₃, protected aminogroup, OH, —OPg^(2m), and halogen; wherein Pg^(2m) is a hydroxylprotecting group;

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl;

wherein the alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, halogen, or substitutedheteroaryl;

R^(5a) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —NH₂, —CN, CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j); wherein Pg^(2j) is a hydroxyl protecting group;

R^(7a), R^(7b), and R^(7c) are, independently, H, OH, —OR⁷¹ or —OPg²;

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl;

wherein Pg² is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, of

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

N^(1q) is —NHPg^(1q), —NH₂, or N₃, wherein Pg^(1q) is an aminoprotecting group;

N^(1r) is —NHPg^(1r), —NH₂, or N₃, wherein Pg^(1r) is an aminoprotecting group;

N^(1g) is —NHPg^(1g), —NH₂, or N₃, wherein Pg^(1g) is an aminoprotecting group;

N^(1h) is —NHPg^(1h), —NH₂, or N₃, wherein Pg^(1h) is an aminoprotecting group;

Pg^(2g) is H or a hydroxyl protecting group;

Pg^(2h) is H or a hydroxyl protecting group;

N^(1p) is —NHPg^(1p), —NH₂, or N₃, wherein Pg^(1p) is an aminoprotecting group;

wherein at least one of N^(1g), N^(1r), N^(1g), N^(1h) is not NH₂ orwherein at least one of PG^(2g) or Pg^(2h) is not H or wherein X⁶ is not—OH or —NH₂;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2.

The present disclosure provides a compound of formula ABCD-4′:

and salts, solvates, enantiomers, and diastereomers thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H, alkyl,amino protecting group, or hydroxyl protecting group; wherein the C₁-C₆alkyl or alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of aryl, halogen, —OR³⁰,—NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X⁶ is selected from the group consisting of H, NH₂, N₃, protected aminogroup, OH, —OPg^(2m), and halogen; wherein Pg^(2m) is a hydroxylprotecting group;

R^(4aa) and R^(4bb) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H, alkyl, CONH₂, or—COCH₃; wherein the alkyl is unsubstituted or substituted with one ormore substituents selected from the group consisting of —CONH₂, —OH,—NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen, andsubstituted heteroaryl;

R^(5aa) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —OC(O)CH₃, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j); wherein Pg^(2j) is a hydroxyl protecting group;

R^(7a), R^(7b), and R^(7c) are, independently, H, OH, —OR⁷¹ or —OPg²;

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl;

wherein Pg² is a hydroxyl protecting group;

N^(1s) is N₃ or —NR^(8a)R^(8b);

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(8b) is H or C1-C3alkyl;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

N^(1q) is —OH, protected hydroxyl group, —NHPg^(1q), N(Pg¹92, —NH₂, orN₃, wherein each Pg^(1q) is independently an amino protecting group;

N^(1r) is —NHPg^(1r), —NH₂, or N₃, wherein Pg^(1r) is an aminoprotecting group;

N^(1g) is —NHPg^(1g), —NH₂, or N₃, wherein Pg^(1g) is an aminoprotecting group;

N^(1h) is —NHPg^(1h), —NH₂, or N₃, wherein Pg^(1h) is an aminoprotecting group;

Pg^(2g) is H or a hydroxyl protecting group;

Pg^(2h) is H or a hydroxyl protecting group;

wherein at least one of N^(1q), N^(1r), N^(1h) is not NH₂ or wherein atleast one of PG^(2g) or Pg^(2h) is not H or wherein X⁶ is not —OH or—NH₂;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2.

In some embodiments, the compound of the present disclosure is selectedfrom the group consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

In some embodiments, the compound of the present disclosure is selectedfrom the group consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

In some embodiments, the compound of the present disclosure is selectedfrom the group consisting of:

r a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

In some embodiments, the compound of the present disclosure is selectedfrom the group consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

In some embodiments, the compound of the present disclosure is

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

In some embodiments, the compound of the present disclosure is

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

In some embodiments, the compound of the present disclosure is selectedfrom the group consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

In some embodiments, the compound of the present disclosure is selectedfrom the group consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

In some embodiments, the compound of the present disclosure is selectedfrom the group consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

In some embodiments, the compound of the present disclosure is selectedfrom the group consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

In some embodiments, the compound of the present disclosure is selectedfrom the group consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

In some embodiments, the compound of the present disclosure is selectedfrom the group consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

In some embodiments, the compound of the present disclosure is selectedfrom the group consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

In some embodiments, the compound of the present disclosure is selectedfrom the group consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

In some embodiments, the compound of the present disclosure is selectedfrom the group consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

In some embodiments, the compound of the present disclosure is selectedfrom the group consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

In some embodiments, the compound of the present disclosure is selectedfrom the group consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

In some embodiments, the compound of the present disclosure is selectedfrom the group consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

In some embodiments, the compound of the present disclosure is selectedfrom the group consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

In some embodiments, the compound of the present disclosure is selectedfrom the group consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

In some embodiments, the compound of the present disclosure is selectedfrom the group consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

In some embodiments, the compound of the present disclosure is selectedfrom the group consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

In some embodiments, the compound of the present disclosure is:

or a salt, solvate, enantiomer, or diastereomer thereof.

In some embodiments, the compound of the present disclosure is:

or a salt, solvate, enantiomer, or diastereomer thereof.

In some embodiments, the compound of the present disclosure is selectedfrom the group consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

In some embodiments, the compound of the present disclosure is selectedfrom the group consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

In some embodiments, the compound of the present disclosure is selectedfrom the group consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

In some embodiments, the compound of the present disclosure is selectedfrom the group consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

Methods of Treatment

Provided herein are also methods of using compounds of formulae AB-2 andABC-2, or a pharmaceutically acceptable salt, solvate, stereoisomer, ortautomer of any of these. In particular, provided is a method oftreating a bacterial infection in a mammal, comprising administering toa mammal in need thereof a therapeutically effective amount of acompound of formulae AB-2 and ABC-2, or a pharmaceutically acceptablesalt, solvate, stereoisomer, or tautomer thereof. Provided is a methodof treating a bacterial infection in a mammal, comprising administeringto a mammal in need thereof a therapeutically effective amount of apharmaceutical composition comprising a compound of formulae AB-2 andABC-2, or a pharmaceutically acceptable salt, solvate, stereoisomer, ortautomer thereof, and a pharmaceutically acceptable excipient. In someembodiments, the mammal is a human.

The bacterial infection may be a gram-positive or gram-negativebacterial infection. The bacterial infection may be infection of aerobicor anaerobic bacteria. The infection may be an infection of one or morespecies selected from the group consisting of Staphylococcus,Lactobacillus, Streptococcus, Sarcina, Escherichia, Enterobacter,Klebsiella, Pseudomonas, Acinetobacter, Mycobacterium, Proteus,Campylobacter, Citrobacter, Nisseria, Baccillus, Bacteroides,Peptococcus, Clostridium, Salmonella, Shigella, Serratia, Haemophilus,Brucella, Francisella, Anthracis, Yersinia, Corynebacterium, Moraxella,and Enterococcus.

Bacterial infections susceptible to treatment according to the presentdisclosure may include primary infections and co-infections caused by aspecies of bacteria and one or more additional infectious agents suchas, for example, bacteria, virus, parasite and fungus.

In yet a further aspect, provided herein is the use of a compoundformulae AB-2 and ABC-2, or a pharmaceutically acceptable salt, solvate,stereoisomer, or tautomer thereof., in the manufacture of a medicamentfor treating a bacterial infection in a subject in need thereof.

In still a further aspect, provided herein is a compound formulae AB-2and ABC-2, or a pharmaceutically acceptable salt, solvate, stereoisomer,or tautomer thereof., for use in a method of treating a bacterialinfection in a subject in need thereof.

Pharmaceutical Compositions

For the purposes of administration, the compounds of the presentdisclosure may be administered as a raw chemical or may be formulated aspharmaceutical compositions. Pharmaceutical compositions of the presentdisclosure comprise a compound of formula AB-2 or ABC-2, or apharmaceutically acceptable salt, solvate, stereoisomer, or tautomer ofany of these, and a pharmaceutically acceptable carrier, diluent orexcipient. The compound of formula AB-2 or ABC-2, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or tautomer of any of these, ispresent in the composition in an amount that is effective to treat aparticular disease or condition of interest—for example, in an amountsufficient to treat a bacterial infection, and generally with acceptabletoxicity to the patient. The antibacterial activity of compounds offormula AB-2 or ABC-2, or a pharmaceutically acceptable salt, solvate,stereoisomer, or tautomer of any of these, can be determined by oneskilled in the art, for example, as described in the Examples below.Appropriate concentrations and dosages can be readily determined by oneskilled in the art.

Administration of the compounds of the disclosure, such as compounds offormula AB-2 or ABC-2, or a pharmaceutically acceptable salt, solvate,stereoisomer, or tautomer of any of these, in pure form or in anappropriate pharmaceutical composition can be carried out via any of theaccepted modes of administration of agents for serving similarutilities. The pharmaceutical compositions of the disclosure can beprepared by combining a compound of the disclosure with an appropriatepharmaceutically acceptable carrier, diluent or excipient, and may beformulated into preparations in solid, semi solid, liquid or gaseousforms, such as tablets, capsules, powders, granules, ointments,solutions, suppositories, injections, inhalants, gels, microspheres, andaerosols. Typical routes of administering such pharmaceuticalcompositions include, without limitation, oral, topical, transdermal,inhalation, parenteral, sublingual, buccal, rectal, vaginal, andintranasal. The term parenteral as used herein includes subcutaneousinjections, intravenous, intramuscular, intrasternal injection orinfusion techniques. Pharmaceutical compositions of the disclosure canbe formulated so as to allow the active ingredients contained therein tobe bioavailable upon administration of the composition to a patient.Compositions that will be administered to a subject or patient take theform of one or more dosage units, where for example, a tablet may be asingle dosage unit, and a container of a compound of the disclosure inaerosol form may hold a plurality of dosage units. Actual methods ofpreparing such dosage forms are known, or will be apparent, to thoseskilled in this art; for example, see Remington: The Science andPractice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy andScience, 2000).

Exemplary Embodiments

Some embodiments of this disclosure are Embodiment I, as follows:

Embodiment I-1. A process for preparing a compound of formula A-5,

wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²²,d R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X¹ is F, —Cl, —Br, or —I;

LVG¹ is a leaving group;

N^(1a) is —NHPg^(1a) or N₃, wherein Pg^(1a) is an amino protectinggroup;

m is zero, 1, or 2;

n is zero, 1, or 2; and,

-   -   wherein m+n is 1, 2 or 3;

or a salt, solvate, enantiomer, or diastereomer thereof, comprising:

(a) contacting a compound of formula A-1:

or a salt, solvate, enantiomer, or diastereomer thereof, with a chiralauxiliary reagent to yield a compound of formula A-2:

or a salt, solvate, enantiomer, or diastereomer thereof,

wherein Xc is a chiral auxiliary group;

(b) contacting the compound of formula A-2 with a Grignard ororganolithium reagent to yield a compound of formula A-3:

or a salt, solvate, enantiomer, or diastereomer thereof,

(c) contacting the compound of formula A-3 with a halogen reagent inpresence of a nucleophile reagent (Nuc-1) to yield a compound of formulaA-4:

or a salt, solvate, enantiomer, or diastereomer thereof; wherein

X¹ is —F, —Cl, —Br, or —I;

Nuc-1 is LVG¹-M, wherein M is H, a metal cation, a non-metal cation, ora lone pair of electrons;

LVG¹ is a leaving group;

(d) exchanging the chiral auxiliary group for an amino protecting groupin the compound of formula A-4 by reaction with an amino protectinggroup reagent to yield the compound of formula A-5:

or a salt, solvate, enantiomer, or diastereomer thereof,

wherein N^(1a) is —NHPg^(1a) or N₃, wherein Pg^(1a) is an aminoprotecting group.

Embodiment I-2. The process of Embodiment I-1, wherein, when X¹ is not—NH₂, —N₃, a protected amino group, further comprising after step (d):

(e) converting X¹ in the compound of formula A-5 to X to yield acompound of formula A-6:

or a salt, solvate, enantiomer, or diastereomer thereof, wherein X is—NH₂, —N₃, a protected amino group, —OH, or protected hydroxyl group.

Embodiment I-3. A process for preparing a compound of formula A-5a,

wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), and R^(3a) are independently selected from the groupconsisting of H, —OR²⁷, —NR²⁸R²⁹ , halogen, C₁-C₄ cycloalkyl, and C₁-C₆alkyl, wherein the alkyl is unsubstituted or substituted with one ormore substituents selected from the group consisting of halogen, —OR³⁰,—NR³¹R³², —SR³³, and —SOR³⁴;

wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3b) is H;

N^(1b) is —NHPg^(1b) or N₃, wherein Pg^(1b) is an amino protectinggroup;

X² is F, —Cl, —Br, or —I;

LVG² is a leaving group.

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

or a salt, solvate, enantiomer, or diastereomer thereof, comprising:

(a) converting —OH in the compound of formula A-7

or a salt, solvate, enantiomer, or diastereomer thereof, to R^(3a) toyield a compound of formula A-8:

or a salt, solvate, enantiomer, or diastereomer thereof, wherein

(b) contacting the compound of formula A-8 with a halogen reagent inpresence of a nucleophile reagent (Nuc-2) to yield a compound of formulaA-5a:

or a salt, solvate, enantiomer, or diastereomer thereof;

wherein

X² is —F, —Cl, —Br, or —I;

Nuc-2 is LVG²-M, wherein M is H, a metal cation, a non-metal cation, ora lone pair of electrons;

LVG² is a leaving group.

Embodiment I-4. The process of Embodiment I-3, wherein when X² is not—NH₂, —N₃, a protected amino group, —OH, or protected hydroxyl group,further comprising after step (b):

(c) converting X² in the compound of formula A-5a to X to yield acompound of formula A-6a:

or a salt, solvate, enantiomer, or diastereomer thereof;

wherein X is —NH₂, —N₃, a protected amino group, —OH, or protectedhydroxyl group.

Embodiment I-5. The process of any one of Embodiments I-1 to I-4,wherein the stereochemistry in the ring of formulae A-1, A-2, A-3, A-4,A-5, A-5a, A-6, A-6a, A-7, and A-8 is as indicated in formula (A′),wherein

is a single bond or a double bond and wherein

indicates a point of attachment to a hydrogen or a moiety:

Embodiment I-6. A process for preparing a compound of formula B-6:

wherein

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl; wherein thealkyl is unsubstituted or substituted with one or more substituentsselected from the group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl,substituted aryl, heteroaryl, halogen, and substituted heteroaryl;

R⁵ is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl is unsubstitutedor substituted with one or more substituents selected from the groupconsisting of —OH, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2o); wherein Pg^(2o) is a hydroxyl protecting group;

R⁸ is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

N^(1c) is —NHPg^(1c) or N₃, wherein Pg^(1c) is an amino protecting group

Pg^(2b) is a hydroxyl protecting group;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

or a salt, solvate, enantiomer, or diastereomer thereof, comprising:

(a) contacting a compound of formula B-1:

or a salt, solvate, enantiomer, or diastereomer thereof, with an aminoprotecting group reagent and a hydroxyl protecting group reagent toyield a compound of formula B-2:

or a salt, solvate, enantiomer, or diastereomer thereof;

wherein Pg^(2a) is a hydroxyl protecting group;

(b) converting the amino group of the compound of formula B-2 at C1 toan azide group;

(c) converting the azide group of the compound of formula B-2 at C1 to ahydroxyl group;

(d) oxidizing the hydroxyl group of the compound of formula B-2 at C1 toan oxo group to yield a compound of formula B-3:

or a salt, solvate, enantiomer, or diastereomer thereof;

(e) converting the oxo group of the compound of formula B-3 to an iminogroup and contacting with an amino reactive reagent to yield a compoundof formula B-4:

or a salt, solvate, enantiomer, or diastereomer thereof;

(f) contacting the compound of formula B-4 with a Grignard ororganolithium reagent to yield a compound of formula B-5:

or a salt, solvate, enantiomer, or diastereomer thereof,

(g) forming a hydroxyl group by selective removal of the Pg^(2a)protecting group of the compound of formula B-6 to yield the compound offormula B-7:

or a salt, solvate, enantiomer, or diastereomer thereof.

Embodiment I-7. A process for preparing a compound of formula B-11:

wherein

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl; wherein thealkyl is unsubstituted or substituted with one or more substituentsselected from the group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl,substituted aryl, heteroaryl, halogen, and substituted heteroaryl;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2o); wherein Pg^(2o) is a hydroxyl protecting group;

R⁸ is H, C₁-C₆ alkyl, an amino protecting group, or

-   -   wherein    -   Q¹ is NH, O, or S;    -   z is an integer from 0 to 4,    -   R^(35z) is H or C₁-C₃ alkyl;    -   each R^(36z) and R^(37z) is independently selected from the        group consisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

N^(1d) is _(—NHPg) ^(1d) or N₃, wherein Pg^(1d) is an amino protectinggroup;

Pg^(2d) is a hydroxyl protecting group;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

or a salt, solvate, enantiomer, or diastereomer thereof, comprising:

(a) contacting a compound of formula B-8:

or a salt, solvate, enantiomer, or diastereomer thereof, with an aminoprotecting group reagent and a first selective hydroxyl protecting groupreagent and a second selective hydroxyl protecting group reagent and anamino reactive reagent to yield a compound of formula B-9:

or a salt, solvate, enantiomer, or diastereomer thereof; wherein Pg^(2c)is a hydroxyl protecting group;

(b) contacting the compound of formula B-9 with a electrophilic reagentto yield a compound of formula B-10:

or a salt, solvate, enantiomer, or diastereomer thereof,

c) forming a hydroxyl group by selective removal of the Pg^(2c)protecting group of the compound of formula B-10 to yield the compoundof formula B-11:

or a salt, solvate, enantiomer, or diastereomer thereof.

Embodiment I-8. The process of any one of Embodiments I-6 to I-7,wherein the stereochemistry in the ring of formulae B-1, B-2, B-3, B-4,B-5, B-6, B-8, B-9, B-10, and B-11, is as indicated in formula (B′),wherein

indicates a point of attachment to a hydrogen or a moiety:

Embodiment I-9. A process for preparing a compound of formula AB-1,

wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴, R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl;

wherein the alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, halogen, and substitutedheteroaryl;

R^(5a) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2m); wherein Pg^(2m) is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

-   -   wherein    -   Q¹ is NH, O, or S;    -   z is an integer from 0 to 4,    -   R^(35z) is H or C₁-C₃ alkyl;    -   each R^(36z) and R^(37z) is independently selected from the        group consisting of H, alkyl, halogen, and —OH, and    -   R^(38z) is H, alkyl, or C(═NH)NR^(39z)R^(40z), wherein R^(39z)        and R^(40z) are independently H or C₁-C₃ alkyl; or

R³⁵z and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

N^(1e) is —NHPg^(1e) or N₃, wherein Pg^(1e) is an amino protectinggroup;

N^(1f) is —NHPg^(1f) or N₃, wherein Pg^(1f) is an amino protectinggroup;

Pg^(2e) is a hydroxyl protecting group;

X is —NH₂, —N₃, protected amino group, —OH, or protected hydroxyl group;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3;

or a salt, solvate, enantiomer, or diastereomer thereof, comprising:

(a) contacting a compound of formula A-9:

wherein LVG³ is a leaving group, with a compound of formula B-12:

to yield the compound of formula (AB-1).

Embodiment I-10. The process of Embodiment I-9, further comprising afterstep (a):

(b) if amino protecting groups and hydroxyl protecting groups arepresent, remove the amino protecting groups and hydroxyl protectinggroups to yield a compound of formula AB-2, or a salt, solvate,enantiomer, or diastereomer thereof

Embodiment I-11. The process of any one of Embodiments I-9 to I-10,wherein the stereochemistry of the compound of formula AB, or a salt,solvate, enantiomer, or diastereomer thereof, — is as indicated informula (AB′):

Embodiment I-12. The process of Embodiment I-9, further comprising afterstep (a):

(b) selectively deprotecting the compound of formula AB-1 by removingthe Pg^(2e) moiety to yield a compound of formula AB-3:

or a salt, solvate, enantiomer, or diastereomer thereof;

(c) contacting the compound of formula AB-3 with a compound of formulaC-1,

or a salt, solvate, enantiomer, or diastereomer thereof, wherein

R^(7a), R^(7b), and R^(7c) are, independently, H, NH₂, OH, —OR⁷¹ or—OPg^(2r);

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen,and substituted heteroaryl;

wherein Pg^(2r) is a hydroxyl protecting group;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R¹⁰ and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

Pg^(2f) is a hydroxyl protecting group;

LVG⁴ is a leaving group;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q +r is 1, 2 or 3;

to yield a compound of formula ABC-1, or a salt, solvate, enantiomer, ordiastereomer thereof,

Embodiment I-13. The process of Embodiment I-12, further comprisingafter step (c):

(d) if amino protecting groups and hydroxyl protecting groups arepresent, remove the amino protecting groups and hydroxyl protectinggroups to yield a compound of formula ABC-2, or a salt, solvate,enantiomer, or diastereomer thereof,

Embodiment I-14. The process of any one of Embodiments I-12 to I-13,wherein the stereochemistry in the ring of formulae ABC-1 and ABC-2, isas indicated in formula (ABC′),

Embodiment I-15. The process of Embodiment I-9, further comprising afterstep (a):

(b) selectively deprotecting the compound of formula AB-1 by removingthe Pg^(2e) moiety to yield a compound of formula AB-3:

or a salt, solvate, enantiomer, or diastereomer thereof;

(c) contacting the compound of formula AB-3 with a compound of formulaCD-1,

or a salt, solvate, enantiomer, or diastereomer thereof, wherein

R^(7a), R^(7b), and R^(7c) are, independently, H, NH₂, OH, —OR⁷¹ or—OPg^(2r);

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, halogen,and substituted heteroaryl;

wherein Pg^(2r) is a hydroxyl protecting group;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

LVG⁵ is a leaving group;

N^(1g) is —NHPg^(1g) or N₃, wherein Pg^(1g) is an amino protectinggroup;

N^(1h) is —NHPg^(1h) or N₃, wherein Pg^(1h) is an amino protectinggroup;

Pg^(2g) is a hydroxyl protecting group;

Pg^(2h) is a hydroxyl protecting group;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3;

to yield a compound of formula ABCD-1, or a salt, solvate, enantiomer,or diastereomer thereof,

Embodiment I-16. The process of Embodiment I-15, further comprisingafter step (c):

(d) if amino protecting groups and hydroxyl protecting groups arepresent, remove the amino protecting groups and hydroxyl protectinggroups to yield a compound of formula ABCD-2, or a salt, solvate,enantiomer, or diastereomer thereof,

Embodiment I-17. The process of any one of Embodiments I-15 to I-16,wherein the stereochemistry in the ABCD ring are indicated as in formula(ABCD'):

Embodiment I-18. A compound of formula A-10:

or a salt, solvate, enantiomer, or diastereomer thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,−SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²²,d R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵,and —OR¹⁶;

R^(2a), R^(2b), R³ and R^(3b) are independently selected from the groupconsisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, and C₁-C₆alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X³ is selected from the group consisting of H, NH₂, N₃, protected aminogroup, OH, —OPg^(2i), and halogen; wherein Pg^(2i) is a hydroxylprotecting group;

LVG⁶ is a leaving group;

N^(1i) is —NHPg^(1i)—NH₂, or N₃, wherein Pg^(1i) is an amino protectinggroup;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3.

Embodiment I-19. The compound of Embodiment I-18, selected from thegroup consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

Embodiment I-20. The compound of Embodiment I-18, selected from thegroup consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

Embodiment I-21. A compound of formula B-13:

or a salt, solvate, enantiomer, or diastereomer thereof, wherein

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl; wherein thealkyl is unsubstituted or substituted with one or more substituentsselected from the group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl,substituted aryl, heteroaryl, halogen, and substituted heteroaryl;

R^(5a) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of OH, —NH₂, —CN, CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH2, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j); wherein Pg^(2j) is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(49z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R¹¹ is H, alkyl, —COCH₃, or a hydroxyl protecting group;

N^(1j) is —NHPg^(1j), —NH₂, or N₃, wherein Pg^(1j) is an aminoprotecting group;

Pg^(2s) is H or hydroxyl protecting group;

o is zero, 1, or 2;

p is zero, 1, or 2;

wherein o+p is 1, 2 or 3.

Embodiment I-22. The compound of Embodiment I-21, being

or a salt, solvate, enantiomer, or diastereomer thereof.

Embodiment I-23. The compound of Embodiment I-21, being

or a salt, solvate, enantiomer, or diastereomer thereof.

Embodiment I-24. A compound of formula AB-4:

or a salt, solvate, enantiomer, or diastereomer thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴, R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X⁴ is selected from the group consisting of H, NH₂, N₃, protected aminogroup, OH, —OPg^(2k), and halogen; wherein Pg^(2k) is a hydroxylprotecting group;

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl; wherein thealkyl is unsubstituted or substituted with one or more substituentsselected from the group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl,substituted aryl, heteroaryl, halogen, or substituted heteroaryl;

R^(5a) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j);

wherein Pg^(2j) is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R¹¹ is H, alkyl, —COCH₃, or a hydroxyl protecting group;

N^(1m) is —NHPg^(1m), —NH₂, or N₃, wherein Pg^(1m) is an aminoprotecting group;

N^(1n) is —NHPg^(1n), —NH₂, or N₃, wherein Pg^(1n) is an aminoprotecting group;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3.

Embodiment I-25. The compound of Embodiment I-24, selected from thegroup consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

Embodiment I-26. The compound of Embodiment I-24, selected from thegroup consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

Embodiment I-27. A compound of formula AB-5:

wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵ and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl;

wherein the alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, halogen, and substitutedheteroaryl;

R^(5a) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2m); wherein Pg^(2m) is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

-   -   wherein    -   Q¹ is NH, O, or S;    -   z is an integer from 0 to 4,    -   R^(35z) is H or C₁-C₃ alkyl;    -   each R^(36z) and R^(37z) is independently selected from the        group consisting of H, alkyl, halogen, and —OH, and    -   R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z)        and R^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

N^(1e) is —NHPg^(1e) or N₃, wherein Pg^(1e) is an amino protectinggroup;

N^(1f) is —NHPg^(1f) or N₃, wherein Pg^(1f) is an amino protectinggroup;

Pg^(2e) is a hydroxyl protecting group;

X is —NH₂, —N₃, protected amino group, —OH, or protected hydroxyl group;

wherein at least one of N^(1e) and N^(1f) is not NH₂ or wherein PG^(2e)is not H or wherein X is not —OH or —NH₂;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3.

Embodiment I-28. The compound of Embodiment I-27, selected from thegroup consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

Embodiment I-29. The compound of the Embodiment I-27, selected from thegroup consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

Embodiment I-30. A compound of formula AB-1:

wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, —NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl;

wherein the alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, halogen, and substitutedheteroaryl;

R^(5a) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2m); wherein Pg^(2m) is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

-   -   wherein    -   Q¹ is NH, O, or S;    -   z is an integer from 0 to 4,    -   R^(35z) is H or C₁-C₃ alkyl;    -   each R^(36z) and R^(37z) is independently selected from the        group consisting of H, alkyl, halogen, and OH, and    -   R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z)        and R^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) _(and R) ^(38z), together with the atoms to which they areattached, form a heterocycloalkyl group comprising at least one N;

N^(1e) is —NHPg^(1e) or N₃, wherein Pg^(1e) is an amino protectinggroup;

N^(1f) is —NHPg^(1f) or N₃, wherein Pg^(1f) is an amino protectinggroup;

Pg^(2e) is a hydroxyl protecting group;

X is —NH₂, —N₃, protected amino group, —OH, or protected hydroxyl group;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3.

Embodiment I-31. A compound of formula (AB-2)

wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴, R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴° , R⁴¹, and R⁴² are independently H or alkyl;

wherein the alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, halogen, and substitutedheteroaryl;

R^(5a) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2m); wherein Pg^(2m) is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(49z), wherein R^(39z) andR^(49z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

X is NH2 or —OH;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3.

Embodiment I-32. The compound of Embodiment I-30, selected from thegroup consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

Embodiment I-33. The compound of Embodiment I-30, selected from thegroup consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

Embodiment I-34. A compound of formula (ABC-3)

or a salt, solvate, enantiomer, or diastereomer thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵,and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X⁵ is selected from the group consisting of H, NH₂, N₃, protected aminogroup, OH, —OPg²¹, and halogen; wherein Pg²¹ is a hydroxyl protectinggroup;

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl; wherein thealkyl is unsubstituted or substituted with one or more substituentsselected from the group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl,substituted aryl, heteroaryl, halogen, and substituted heteroaryl;

R^(5a) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j);

wherein Pg^(2j) is a hydroxyl protecting group;

R^(7a), R^(7b), and R^(7c) are, independently, H, OH, —OR⁷¹ or —OPg²;

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl;

wherein Pg² is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR ^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

N^(1o) is —NHPg^(1o), —NH₂, or N₃, wherein Pg^(1o) is an aminoprotecting group;

N^(1p) is —NHPg^(1p), —NH₂, or N₃, wherein Pg^(1p) is an aminoprotecting group;

Pg^(2f) is a hydroxyl protecting group or H;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3.

Embodiment I-35. A compound of formula (ABC-4)

or a salt, solvate, enantiomer, or diastereomer thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵,and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X is —NH₂, —N₃, protected amino group, —OH, or protected hydroxyl group;

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl; wherein thealkyl is unsubstituted or substituted with one or more substituentsselected from the group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl,substituted aryl, heteroaryl, halogen, and substituted heteroaryl;

R^(5a) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j);

wherein Pg^(2j) is a hydroxyl protecting group;

R^(7a), R^(7b), and R^(7c) are, independently, H, OH, —OR⁷¹ or —OPg²;

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl;

wherein Pg² is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(49z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

N^(1e) is —NHPg^(1e) or N₃, wherein Pg^(1e) is an amino protectinggroup;

N^(1f) is —NHPg^(1f) or N₃, wherein Pg^(1f) is an amino protectinggroup;

Pg^(2f) is a hydroxyl protecting group or H;

wherein at least one of N^(1e) and N^(1f) is not NH₂ or wherein Pg^(2f)is not H or wherein X is not —OH or —NH₂;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3.

Embodiment I-36. A compound of formula (ABC-1)

or a salt, solvate, enantiomer, or diastereomer thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, −N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁹R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X is —NH₂, —N₃, protected amino group, —OH, or protected hydroxyl group;

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl; wherein thealkyl is unsubstituted or substituted with one or more substituentsselected from the group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl,substituted aryl, heteroaryl, halogen, and substituted heteroaryl;

R^(5a) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j);

wherein Pg^(2j) is a hydroxyl protecting group;

R^(7a), R^(7b), and R^(7c) are, independently, H, OH, —OR⁷¹ or —OPg²;

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl;

wherein Pg² is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

N^(1o) is —NHPg^(1o) or N₃, wherein Pg^(1o) is an amino protectinggroup;

N^(1p) is —NHPg^(1p) or N₃, wherein Pg^(1p) is an amino protectinggroup;

Pg^(2f) is a hydroxyl protecting group;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3.

Embodiment I-37. A compound of formula (ABC-2)

or a salt, solvate, enantiomer, or diastereomer thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X is —NH₂ or —OH;

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl; wherein thealkyl is unsubstituted or substituted with one or more substituentsselected from the group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl,substituted aryl, heteroaryl, halogen, and substituted heteroaryl;

R^(5a) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j); wherein Pg^(2j) is a hydroxyl protecting group;

R^(7a), R^(7b), and R^(7c) are, independently, H, OH, —OR⁷¹ or —OPg²;

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl;

wherein Pg² is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3.

Embodiment I-38. The compound of Embodiment I-34, selected from thegroup consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

Embodiment I-39. The compound of Embodiment I-34, selected from thegroup consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

Embodiment I-40. A compound of formula (ABCD-3)

or a salt, solvate, enantiomer, or diastereomer thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴, R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X⁶ is selected from the group consisting of H, NH₂, N₃, protected aminogroup, OH, —OPg^(2m), and halogen; wherein Pg^(2m) is a hydroxylprotecting group;

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl;

wherein the alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, halogen, and substitutedheteroaryl;

R^(5a) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j); wherein Pg^(2j) is a hydroxyl protecting group;

R^(7a), R^(7b), and R^(7c) are, independently, H, OH, —OR⁷¹ or —OPg²;

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting of—CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl;

wherein Pg² is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

N^(1q) is —NHPg^(1q) or N₃, wherein Pg^(1q) is an amino protectinggroup;

N^(1r) is —NHPg^(1r) or N₃, wherein Pg^(1r) is an amino protectinggroup;

N^(1g) is —NHPg^(1g) or N₃, wherein Pg^(1g) is an amino protectinggroup;

N^(1h) is —NHPg^(1h) or N₃, wherein Pg^(1h) is an amino protectinggroup;

Pg^(2g) is a hydroxyl protecting group;

Pg^(2h) is a hydroxyl protecting group;

wherein at least one of N^(1q), N^(1r), N^(1g), N^(1h) is not NH₂ orwherein at least one of PG^(2g) or Pg^(2h) is not H or wherein X⁶ is not—OH or —NH₂;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2;

-   -   wherein q+r is 1, 2 or 3.

Embodiment I-41. A compound of formula ABCD-4:

or a salt, solvate, enantiomer, or diastereomer thereof, wherein

R^(1a) and R^(1b) are independently selected from the group consistingof H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl, and heteroaryl, wherein thealkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR¹², —SO₂R¹³,—OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, and

wherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; or

R^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and

wherein each R²², R²³, R²⁴, R²⁵, and R²⁶ is independently H or alkyl,wherein the alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶;

R^(2a), R^(2b), R^(3a) and R^(3b) are independently selected from thegroup consisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, andC₁-C₆ alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H or alkyl;wherein the C₁-C₆ alkyl or alkyl is unsubstituted or substituted withone or more substituents selected from the group consisting of halogen,—OR³⁰, —NR³¹R³², —SR³³, and —SO₂R³⁴;

wherein each R³⁰, R³¹, R³², R³³, and R³⁴ is independently H or alkylsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; or

R^(2a) and R^(2b) form an oxo or imino group substituted with C₁-C₆alkyl;

R^(3a) and R^(3b) form an oxo or imino group substituted with C₁-C₆alkyl;

X⁶ is selected from the group consisting of H, NH₂, N₃, protected aminogroup, OH, —OPg^(2m), and halogen; wherein Pg^(2m) is a hydroxylprotecting group;

R^(4a) and R^(4b) are, independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², orhalogen;

wherein each R⁴⁰, R⁴¹, and R⁴² are independently H or alkyl;

wherein the alkyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, halogen, and substitutedheteroaryl;

R^(5a) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —NH₂, —CN, —CONH₂, and halogen;

R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2j); wherein Pg^(2j) is a hydroxyl protecting group;

R^(7a), R^(7b), and R^(7c) are, independently, H, OH, —OR⁷¹ or —OPg²;

wherein R⁷¹ is alkyl; wherein the alkyl is unsubstituted or substitutedwith one or more substituents selected from the group consisting ofCONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl;

wherein Pg² is a hydroxyl protecting group;

R^(8a) is H, C₁-C₆ alkyl, an amino protecting group, or

wherein

Q¹ is NH, O, or S;

z is an integer from 0 to 4,

R^(35z) is H or C₁-C₃ alkyl;

each R^(36z) and R^(37z) is independently selected from the groupconsisting of H, alkyl, halogen, and —OH, and

R^(38z) is H, alkyl, or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) andR^(40z) are independently H or C₁-C₃ alkyl; or

R^(35z) and R^(38z), together with the atoms to which they are attached,form a heterocycloalkyl group comprising at least one N;

R^(9a) and R^(9b) are independently H, OH, or —OR⁹¹,

wherein R⁹¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R^(10a) and R^(10b) are independently H, OH, or —OR¹⁰¹,

wherein R¹⁰¹ is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl,and alkynyl is unsubstituted or substituted with one or moresubstituents selected from the group consisting of —CONH₂, —OH, —NH₂,—COCH₃, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

N^(1q) is —NHPg^(1q), —NH₂, or N₃, wherein Pg^(1q) is an aminoprotecting group;

N^(1r) is —NHPg^(1r), —NH₂, or N₃, wherein Pg^(1r) is an aminoprotecting group;

N^(1g) is —NHPg^(1g), —NH₂, or N₃, wherein Pg^(1g) is an aminoprotecting group;

N^(1h) is —NHPg^(1h), —NH₂, or N₃, wherein Pg^(1h) is an aminoprotecting group;

Pg^(2g) is H or a hydroxyl protecting group;

Pg^(2h) is H or a hydroxyl protecting group;

N^(1p) is —NHPg^(1p), —NH₂, or N₃, wherein Pg^(1p) is an aminoprotecting group;

wherein at least one of N^(1q), N^(1r), N^(1g), N^(1h) is not NH₂ orwherein at least one of PG^(2g) or Pg^(2h) is not H or wherein X⁶ is not—OH or —NH₂;

m is zero, 1, or 2;

n is zero, 1, or 2;

-   -   wherein m+n is 1, 2 or 3;

o is zero, 1, or 2;

p is zero, 1, or 2;

-   -   wherein o+p is 1, 2 or 3;

q is zero, 1, or 2;

r is zero, 1, or 2.

Embodiment I-42. The compound of Embodiment I-40, selected from thegroup consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

Embodiment I-43. The compound of Embodiment I-40, selected from thegroup consisting of:

or a salt, solvate, enantiomer, or diastereomer of any of the foregoing.

Embodiment I-44. A pharmaceutical composition, comprising a compound ofany one of Embodiments I-1 to I-43, or a pharmaceutically acceptablesalt, solvate, stereoisomer, or tautomer thereof, and a pharmaceuticallyacceptable carrier.

Embodiment I-45. A method for treating a bacterial infection in asubject, comprising administering to a subject in need thereof atherapeutically effective amount of a compound of any one of EmbodimentI-31 and I-37, or a pharmaceutically acceptable salt, solvate,stereoisomer, or tautomer thereof.

Embodiment I-46. A method for treating a bacterial infection in asubject, comprising administering to a subject in need thereof atherapeutically effective amount of a pharmaceutical compositionaccording to Embodiment I-44.

Embodiment I-47. The method of Embodiment I-45 or Embodiment I-46,wherein the bacterial infection is a gram-negative bacterial infection.

Embodiment I-48. The method of Embodiment I-45 or Embodiment I-46,wherein the bacterial infection is infection of a Staphylococcus,Lactobacillus, Streptococcus, Sarcina, Escherichia, Enterobacter,Klebsiella, Pseudomonas, Acinetobacter, Mycobacterium, Proteus,Campylobacter, Citrobacter, Nisseria, Baccillus, Bacteroides,Peptococcus, Clostridium, Salmonella, Shigella, Serratia, Haemophilus,Brucella, Francisella, Anthracis, Yersinia, Corynebacterium, Moraxella,or Enterococcus species.

Embodiment I-49. Use of a compound of any one of Embodiment I-31 andEmbodiment I-37, or a pharmaceutically acceptable salt, solvate,stereoisomer, or tautomer thereof, in the manufacture of a medicamentfor treating a bacterial infection in a subject in need thereof.

Embodiment I-50. A compound of any one of Embodiment I-31 and EmbodimentI-37, or a pharmaceutically acceptable salt, solvate, stereoisomer, ortautomer thereof, for use in a method of treating a bacterial infectionin a subject in need thereof.

EXAMPLES

The disclosure is further illustrated by the following examples, whichare not to be construed as limiting this disclosure in scope or spiritto the specific procedures herein described. It is to be understood thatthe examples are provided to illustrate certain embodiments and sthat nolimitation to the scope of the disclosure is intended thereby. It is tobe further understood that resort may be had to various otherembodiments, modifications, and equivalents thereof which may suggestthemselves to those skilled in the art without departing from the spiritof the present disclosure and/or scope of the appended claims.

Unless otherwise noted, starting components may be obtained from sourcessuch as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, MatrixScientific, TCI, and Fluorochem USA, etc. or synthesized according tosources known to those skilled in the art (see, for example, AdvancedOrganic Chemistry: Reactions, Mechanisms, and Structure, 5th edition(Wiley, December 2000)) or prepared as described herein.

Example 1

[(2R,3R,4R)-4-acetoxy-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-5-hydroxy-tetrahydrofuran-2-yl]methylacetate

NBS (268 mg, 1.50 mmol) was added to a solution of[(2R,3R,4R,5R)-4-acetoxy-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-5-(p-tolylsulfanyl)tetrahydrofuran-2-yl]methylacetate (638 mg, 1 mmol) in acetone (15.0 mL) under N₂ at 0° C. After 1h, the reaction was quenched with 1:1 sat. NaHCO₃/Na₂S₂O₃ (30.0 mL) andacetone was removed under reduced pressure. The aqueous layer wasextracted with DCM (3×15 mL). The combined organic layers were driedover Na₂SO₄, filtered and concentrated under reduced pressure. Thematerial was purified on silica gel chromatography (25 g, dry loading)using 20% to 60% EtOAc in hexane to provide the title compound as asolid (diastereomers, 400 mg, 71%). LCMS m/z: ES⁺[M-OH]⁺: 513.22,[M+NH₄]⁺: 548.17.

Example 1A

Step 1

(2S,3S,4R,5R,6R)-5-amino-2-(aminomethyl)-6-(((2R,3S,4R)-4-hydroxy-2-(hydroxymethyl)-5-methoxytetrahydrofuran-3-yl)oxy)tetrahydro-2H-pyran-3,4-diol

To a solution of neomycin B sulfate (5.0 g, 8.14 mmol, 1.0 eq) in 6N HCl(40 mL) and MeOH (40 mL)was heated to 90° C. for 8 h, then the solventwas evaporated, and the residue was dissolved in water (20 mL), thenadded MeOH (50 mL) slowly until a lot of precipitate was produced,filtered and the mother liquid was concentrated to afford the crudeproduct (2.8 g) which was used to next step without furtherpurification. LCMS [M+H] ⁺:325.2

Step 2

(2S,3S,4R,5R,6R)-5-amino-2-(aminomethyl)-6-(((2R,3S,4R)-4,5-dihydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)tetrahydro-2H-pyran-3,4-diol

The suspended solution of the crude(2S,3S,4R,5R,6R)-5-amino-2-(aminomethyl)-6-(((2R,3S,4R)-4-hydroxy-2-(hydroxymethyl)-5-methoxytetrahydrofuran-3-yl)oxy)tetrahydro-2H-pyran-3,4-diol(2.8 g, 8.64 mmol, 1.0 eq.) in TFA/H₂O (25 mL/25 mL) was stirred at 40°C. for 18 h, then the solvent was evaporated, and the residue wasdissolved in water (25 mL) and was added MeOH (50 mL) slowly until a lotof precipitate was produced, filtered and the mother liquid wasconcentrated to give the crude product (1.6 g) which was used to nextstep without further purification. LCMS [M+H]⁺: 311.4

Step 3

benzyl((2R,3R,4R,5S,6S)-6-((((benzyloxy)carbonyl)amino)methyl)-2-(((2R,3S,4R)-4,5-dihydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)-4,5-dihydroxytetrahydro-2H-pyran-3-yl)carbamate

To a solution of the crude(2S,3S,4R,5R,6R)-5-amino-2-(aminomethyl)-6-(((2R,3S,4R)-4,5-dihydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)tetrahydro-2H-pyran-3,4-diol(1.6 g, 5.14 mmol, 1.0 eq) in MeOH/H₂O (30 mL/10 mL) was added aq. sat.Na₂CO₃ (3.27 g, 30.84 mmol, 6.0 eq) at 0° C., followed by benzylcarbonochloridate (2.62 g, 15.42 mmol, 3.0 eq). After stirred at r.t.for 18 h, the solvent was removed at reduced pressure and wash withDCM/MeOH=10/1 (20 mL), filtered and the residue was purified by silicagel column chromatography (DCM/MeOH=10/1, v/v) to give the crude product(1.3 g). LCMS [M+Na]⁺: 601.3

Step 4

(3R,4R,5R)-5-(acetoxymethyl)-4-(((2R,3R,4R,5R,6S)-4,5-diacetoxy-3-(((benzyloxy)carbonyl)amino)-6-4((benzyloxy)carbonyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydrofuran-2,3-diyldiacetate

To a solution of the crudebenzyl((2R,3R,4R,5S,6S)-6-((((benzyloxy)carbonyl)amino)methyl)-2-(((2R,3S,4R)-4,5-dihydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)-4,5-dihydroxytetrahydro-2H-pyran-3-yl)carbamate(1.3 g, 2.16 mmol, 1.0 eq.) in pyridine (10 mL) was added Ac₂O (5 mL) indropwise, then the mixture was stirred at r.t. for 18 h. The solvent wasremoved, and the residue was diluted with EA (100 mL), washed with aq.sat. NH₄Cl (50 mL*3), and dried over MgSO₄, and concentrated, purifiedby silica gel column chromatography (PE/EA=2:1, v/v) and prep-HPLC toafford the product (124.5 mg). LCMS [M+Na]⁺: 811.4. ¹H NMR (400 MHz,DMSO-d₆) δ 7.31-7.38 (m, 10 H), 5.82-5.86 (m, 1 H), 4.89-5.09 (m, 7 H),4.62-4.64 (m, 1 H), 4.42-4.47(m, 1 H), 3.67-4.06 (m, 9 H), 1.95-2.08 (m,15H).

Step 5

((2S,3R,4R,5R,6R)-6-(((2R,3R,4R)-4-acetoxy-2-(acetoxymethyl)-5-hydroxytetrahydrofuran-3-yl)oxy)-5-(((benzyloxy)carbonyl)amino)-2-((((benzyloxy)carbonyl)amino)methyl)tetrahydro-2H-pyran-3,4-diyldiacetate)

To the solution of(3R,4R,5R)-5-(acetoxymethyl)-4-(((2R,3R,4R,5R,6S)-4,5-diacetoxy-3-(((benzyloxy)carbonyl)amino)-6-((((benzyloxy)carbonyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydrofuran-2,3-diyldiacetate (170.5 mg, 0.21 mmol, 1.0 eq.) in dry DMF (10 mL) was addedAcOH.NH₃ (64.7 mg, 0.84 mmol, 4.0 eq.), then the mixture was stirred at40° C. for 18 h. The solvent was removed, and the preparation andpurification to afford product (47 mg). LCMS [M+Na]⁺: 769.4. ¹H NMR (400MHz, DMSO-d₆) δ 7.31-7.37 (m, 10 H), 6.95 (m, 1 H),5.81-5.84 (m, 1 H),4.78-5.10 (m, 10 H), 4.27-4.30(m, 1 H), 3.99-4.02 (m, 2 H),3.48-3.52 (m,2H) , 3.06-3.12 (m, 2 H),1.80-2.08 (m, 12 H).

Example 1B

Step 1

(2S,3S,4R,5R,6R)-5-acetamido-2-(acetamidomethyl)-6-(((2R,3S,4R)-5-acetoxy-2-(acetoxymethyl)-4-hydroxytetrahydrofuran-3-yl)oxy)-4-hydroxytetrahydro-2H-pyran-3-ylacetate

The suspended solution of(2S,3S,4R,5R,6R)-5-amino-2-(aminomethyl)-6-(((2R,3S,4R)-4,5-dihydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)tetrahydro-2H-pyran-3,4-diol(3.0 g, 9.65 mmol, 1.0 eq.) in Na₂CO₃ aq (5 mL) was added pyridine (20mL) and Ac₂O (10 mL) in dropwise, then the mixture was stirred at 60° C.for 8 h. The solvent was evaporated, and purified by silica gel columnchromatography (DCM/MeOH=20:1, v/v) to afford the product (1.31 g). LCMS[M+H]⁺: 521.4.

Step 2

(2S,3R,4R,5R,6R)-5-acetamido-2-(acetamidomethyl)-6-(((2R,3R,4R)-4,5-diacetoxy-2-(acetoxymethyl)tetrahydrofuran-3-yl)oxy)tetrahydro-2H-pyran-3,4-diyldiacetate

To a solution of the(2S,3S,4R,5R,6R)-5-acetamido-2-(acetamidomethyl)-6-(((2R,3S,4R)-5-acetoxy-2-(acetoxymethyl)-4-hydroxytetrahydrofuran-3-yl)oxy)-4-hydroxytetrahydro-2H-pyran-3-ylacetate (1.31 g, 2.52 mmol, 1.0 eq.) in pyridine (10 mL) was added Ac₂O(5 mL) in dropwise, then the mixture was stirred at r.t. for 18 h. Thesolvent was removed, and the residue was diluted with EA (30 mL), washedwith aq. sat. NH₄Cl (10 mL*3), and dried over MgSO₄, and concentrated,purified via prep-HPLC to afford the product (177.0 mg). LCMS [M+Na]⁺:827.4. ¹H NMR (400 MHz, DMSO-d₆) δ 7.82-7.84 (m, 0.93 H), 7.39-7.41 (m,0.3 H), 6.79-6.82 (m, 0.34 H), 5.88-5.99 (m, 0.77 H), 5.30-5.31 (m, 0.35H), 4.84-5.13(m, 1 H), 4.80-4.83 (m, 2.33 H), 4.59-4.62 (m, 1 H),4.35-4.37 (m, 0.9 H), 3.75-4.18 (m, 4 H), 3.11-3.29 (m, 2 H), 1.79-2.12(m, 21 H).

Example 2

Step 1

(S)—N-((E)-((S)-3,4-dihydro-2H-pyran-2-yl)methylene)-2-methylpropane-2-sulfinamide

(S)-(+)-2-Methyl-2-propanesulfinamide (50 g, 412 mmol) and CuSO4 (131.7g, 825 mmol) were mixed in DCM (600.0 mL). A solution of2-formyl-3,4-dihydro-2H-pyran (48.6 g, 433 mmol, Synthonix) in DCM(100.0 mL) was added over 20 min. The mixture was stirred at roomtemperature for 18 h, and then filtered through Celite and rinsed withDCM. The filtrate was evaporated under reduced pressure. The materialwas purified on silica gel (5×330 g, dry loading) by MPLC using 0-20%Et₂O in hexane as eluent to provide the title compound (23.74 g, 27%,second eluting diastereomer). ¹H NMR (400 MHz, CDCl₃) δ 8.08 (d, J=3.0Hz, 1H), 6.47 (dt, J=6.3, 1.6 Hz, 1H), 4.81-4.72 (m, 2H), 2.19-1.94 (m,4H), 1.24 (s, 9H).

Step 2

(S)—N—((S)-1-((S)-3,4-dihydro-2H-pyran-2-yl)ethyl)-2-methylpropane-2-sulfinamide

(S)—N-((E)-((S)-3,4-dihydro-2H-pyran-2-yl)methylene)-2-methylpropane-2-sulfinamide(7.30 g, 33.9 mmol) was dissolved in dry DCM (100 mL) and the solutionwas cooled to −78° C. MeMgBr (3.0 M in Et₂O, 22.6 mL, 67.8 mmol) wasadded dropwise to the mixture and stirring was continued at lowtemperature for 2 hours, before allowing the mixture to warm to roomtemperature. Stirring was continued at room temperature for 1 hour.Concentrated aqueous NH₄Cl (50 mL) was added, and the mixture wasextracted with DCM (3×50 mL). The combined organic layers were dried(MgSO₄), and concentrated in vacuo to afford a crude oil containing amixture of diastereomers. The material was purified using silica gelchromatography (120 g cartridge) with hexanes and ethyl acetate (0-100%)to afford the title compound as an oil (4.40 g, 56%). LCMS m/z:ES⁺[M+H]⁺: 232.16.

Step 3

(S)—N-benzyl-N—((S)-1-((S)-3,4-dihydro-2H-pyran-2-yl)ethyl)-2-methylpropane-2-sulfinamide

NaH (60% dispersion, 913 mg, 22.8 mmol) was added to a solution of(S)—N—((S)-1-((S)-3,4-dihydro-2H-pyran-2-yl)ethyl)-2-methylpropane-2-sulfinamide(4.40 g, 19.0 mmol) and benzyl bromide (3.39 mL, 28.5 mmol) in DMF (100mL) at 0° C. The mixture was stirred at this temperature for 2 hours,then brine (100 mL) was added at 0° C. The aqueous layer was extractedwith Et₂O (3×50.0 mL). The combined organic layers were dried (MgSO₄)and concentrated in vacuo to afford a residue that was purified usingsilica gel chromatography (120 g cartridge) using hexanes and ethylacetate (0-100%). The pure fractions were concentrated in vacuo toafford the title compound as an oil (3.50 g, 57%). LCMS m/z: ES⁺ 322.14.

¹H NMR (500 MHz, DMSO) δ 7.45 (d, J=7.1 Hz, 2H), 7.35-7.29 (m, 2H), 7.23(t, J=7.3 Hz, 1H), 6.38 (d, J=6.1 Hz, 1H), 4.65 (ddd, J=6.2, 4.3, 1.4Hz, 1H), 4.35 (d, J=16.5 Hz, 1H), 3.91 (t, J=11.4 Hz, 1H), 3.80 (td,J=9.2, 2.3 Hz, 1H), 3.22-3.11 (m, 1H), 1.97-1.92 (m, 1H), 1.89-1.78 (m,2H), 1.53-1.42 (m, 1H), 1.19 (t, J=3.4 Hz, 3H), 1.10 (s, 8H).

Step 4

(S)—N-benzyl-N-((1S)-1-((2S)-6-hydroxy-5-iodotetrahydro-2H-pyran-2-yl)ethyl)-2-methylpropane-2-sulfinamide

(S)—N-benzyl-N—((S)-1-((S)-3,4-dihydro-2H-pyran-2-yl)ethyl)-2-methylpropane-2-sulfinamide(4.40 g, 13.7 mmol) and NaHCO₃ (3.45 g, 41.1 mmol) were dissolved in H₂O(75.0 mL) and ACN (75.0 mL). 12 (3.82 g, 15.1 mmol) was addedportionwise over 10 minutes at 0° C. The cooling bath was removed, andstirring was continued at room temperature over 90 minutes. The reactionmixture was quenched with a saturated aqueous solution of Na₂S₂O₃ (30.0mL) and extracted with EtOAc (3×20.0 mL). The combined organic layerswere dried (MgSO₄) and concentrated in vacuo to afford the titlecompound as a solid (4.70 g, 74%). LCMS m/z: ES⁺ [M+H]⁺: 466.04.

Step 5

Benzylbenzyl((1S)-1-((2S)-6-hydroxy-5-iodotetrahydro-2H-pyran-2-yl)ethyl)carbamate

(S)—N-benzyl-N-((1S)-1-((2S)-6-hydroxy-5-iodotetrahydro-2H-pyran-2-yl)ethyl)-2-methylpropane-2-sulfinamide(4.70 g, 10.1 mmol) was dissolved in 1,4-dioxane (150 mL), and anaqueous solution of 1 N HCl (25.2 mL, 25.2 mmol) was added. Stirring wascontinued at room temperature for 20 minutes, before solid Na₂CO₃ (8.56g, 80.8 mmol) was added to the mixture. Stirring was continued for 20minutes, and then CbzCl (1.72 mL, 12.1 mmol) was added dropwise.Stirring was continued for 2 hours. Water (200 mL) was added and themixture was extracted with EtOAc (3×50 mL). The combined organic layerswere dried (MgSO₄) and concentrated in vacuo to give a residue that waspurified using silica gel chromatography (80 g cartridge) using hexanesand ethyl acetate (0-100%). The pure fractions were concentrated invacuo to afford the title compound as an oil (3.70 g, 74%). LCMS m/z:ES⁺[M+H]⁺: 518.04.

Step 6

Benzyl((1S)-1-((2S)-5-azido-6-oxotetrahydro-2H-pyran-2-yl)ethyl)(benzyl)carbamate

Benzylbenzyl((1S)-1-((2S)-6-hydroxy-5-iodotetrahydro-2H-pyran-2-yl)ethyl)carbamate(3.70 g, 7.47 mmol) was dissolved in DCM (350 mL). 4 Å molecular sieves(1.00 g) were suspended in the mixture, and PDC (8.43 g, 22.4 mmol) wasadded. Stirring was continued over 24 hours at room temperature, thenfiltered through a pad of celite using ethyl acetate, and concentratedin vacuo to afford crude benzylbenzyl((1S)-1-((2S)-5-iodo-6-oxotetrahydro-2H-pyran-2-yl)ethyl)carbamateas an oil, which was redissolved in DMF (50.0 mL). NaN₃ (971 mg, 14.9mmol) was added as a solid, and stirring was continued for 2 hours atroom temperature. The solvent was removed in vacuo, and the residue wasdissolved in EtOAc (100 mL) and washed with water (3×25 mL). The organiclayer was dried (MgSO₄) and concentrated in vacuo to afford an oil thatwas purified using silica gel chromatography (80 g cartridge) with ethylacetate and hexanes (0-100%). The pure fractions were combined andconcentrated in vacuo to afford the title compound as an oil (1.40 g,46%). LCMS m/z: ES⁺[M+Na]⁺: 431.13; calc: 431.18.

Step 7

Benzyl((1S)-1-((2S)-5-azido-6-hydroxytetrahydro-2H-pyran-2-yl)ethyl)(benzyl)carbamate

Benzyl((1S)-1-((2S)-5-azido-6-oxotetrahydro-2H-pyran-2-yl)ethyl)(benzyl)carbamate(1.40 g, 3.43 mmol) was dissolved in dry DCM (75.0 mL) and the mixturewas cooled to −78° C. A solution of DIBAL-H (1.0 M in toluene, 6.86 mL,6.86 mmol) was added to the mixture, and stirring was continued at lowtemperature for 1 hour. EtOH (2.00 mL) was added dropwise to the coldreaction mixture, which was then poured into a saturated aqueoussolution of Rochelle's salt (200 mL). The mixture was stirred vigorouslyfor 1 hour, then extracted with EtOAc (3×50.0 mL). The combined organiclayers were dried (MgSO₄) and concentrated in vacuo to afford a residuethat was purified using silica gel chromatography (80 g cartridge) withhexanes and ethyl acetate (0-70%). The pure fractions were collected andconcentrated in vacuo to afford the title compound as a mixture ofdiastereomers (800 mg, 57%). LCMS m/z: ES⁺[M+Na]⁺: 433.16; calc: 433.19.

Step 8

(1S,2S,3R,4S,6R)-4,6-diazido-3-(((2R,6S)-3-azido-6-((S)-1-(benzyl((benzyloxy)carbonyl)amino)ethyl)tetrahydro-2H-pyran-2-yl)oxy)cyclohexane-1,2-diyldiacetate

Benzyl((1S)-1-((2S)-5-azido-6-hydroxytetrahydro-2H-pyran-2-yl)ethyl)(benzyl)carbamate(800 mg, 1.95 mmol) and K₂CO₃ (808 mg, 5.85 mmol) were suspended in dryDCM (30.0 mL). CCl₃CN (0.977 mL, 9.75 mmol) was added dropwise to themixture, and stirring was continued over two days. The reaction mixturewas filtered through celite, and rinsed with DCM (25.0 mL). The filtratewas concentrated in vacuo to afford a residue that was redissolved inDCM (10.0 mL).[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-hydroxy-cyclohexyl]acetate(814 mg, 2.73 mmol) was added. The mixture was cooled to −78° C., andBF₃.Et₂O (962 μL, 7.80 mmol) was added dropwise. Stirring was continuedfor 5 hours before the mixture was quenched with saturated aqueousNaHCO₃ (50.0 mL). The mixture was extracted with DCM (3×25.0 mL). Theorganic layers were combined, washed with brine (25.0 mL), dried(MgSO₄), and concentrated in vacuo to afford a crude residue that waspurified using C18 reverse phase chromatography (120 g cartridge). Thepure fractions were concentrated in vacuo to afford the title product asan oil (500 mg, 37%). LCMS m/z: ES⁺[M+Na]⁺: 433.16; calc: 433.19.

Step 9

Benzyl((S)-1-((2S,5R,6R)-5-azido-6-(((1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxycyclohexyl)oxy)tetrahydro-2H-pyran-2-yl)ethyl)(benzyl)carbamate

(1S,2S,3R,4S,6R)-4,6-diazido-3-(((2R,6S)-3-azido-6-((S)-1-(benzyl((benzyloxy)carbonyl)amino)ethyl)tetrahydro-2H-pyran-2-yl)oxy)cyclohexane-1,2-diyldiacetate (0.500 g, 0.724 mmol) was dissolved in MeOH (25.0 mL) andNaOMe (0.235 g, 4.34 mmol) was added as a solid. Stirring was continuedfor 1 hour, then the mixture was quenched with AcOH (5.00 mL). Themixture was concentrated in vacuo, and submitted for SFC purification.The desired diastereomer (5.30 min. elution time) was isolated andobtained as an oil (42 mg, 13%).

Step 10

(1S,2S,3R,4S,6R)-4,6-diazido-3-(((2R,3R,6S)-3-azido-6-((S)-1-(benzyl((benzyloxy)carbonyl)amino)ethyl)tetrahydro-2H-pyran-2-yl)oxy)-2-hydroxycyclohexylacetate

Ac₂O (0.01 mL, 0.05 mmol) was added to a solution of benzyl((S)-1-((2S,5R,6R)-5-azido-6-(((1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxycyclohexyl)oxy)tetrahydro-2H-pyran-2-yl)ethyl)(benzyl)carbamate(28 mg, 0.05 mmol) and pyridine (0.02 mL, 0.3 mmol) in dry DCM (3 mL) atroom temperature. After 22 h, MeOH (0.5 mL) was added and the volatileswere removed under reduced pressure. The material was purified on silicagel (12 g, dry loading) by MPLC using hexane to 40% EtOAc in hexane toprovide the title compound (21 mg, 70%) as a solid. M+H⁺: 649.3.

Step 11

(2S,3R,4R,5R,6R)-6-(((2R,3R,4R,5S)-4-acetoxy-5-(41S,2S,3R,5S,6R)-2-acetoxy-3,5-diazido-6-(((2R,3R,6S)-3-azido-6-((S)-1-(benzyl((benzyloxy)carbonyl)amino)ethyl)tetrahydro-2H-pyran-2-yl)oxy)cyclohexyl)oxy)-2-(acetoxymethyl)tetrahydrofuran-3-yl)oxy)-5-azido-2-(azidomethyl)tetrahydro-2H-pyran-3,4-diyldiacetate

CCl₃ CN (0.04 mL, 0.37 mol) was added dropwise to a mixture of[(2R,3R,4R)-4-acetoxy-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-5-hydroxy-tetrahydrofuran-2-yl]methylacetate (39 mg, 0.07 mmol) and K₂CO₃ (31 mg, 0.22 mmol) in dry DCM (8mL) at room temperature under N₂. The mixture was stirred at roomtemperature for 18 h, then filtered with a filter syringe and rinsedwith DCM. The filtrate was concentrated under reduced pressure.(1S,2S,3R,4S,6R)-4,6-diazido-3-(((2R,3R,6S)-3-azido-6-((S)-1-(benzyl((benzyloxy)carbonyl)amino)ethyl)tetrahydro-2H-pyran-2-yl)oxy)-2-hydroxycyclohexylacetate (16 mg, 0.03 mmol) was dissolved in DCM (8 mL) and added to theprevious reaction mixture. Activated 4 Å molecular sieves were added andthe mixture was cooled to −78° C., then BF₃.OEt₂ (0.02 mL, 0.12 mmol)was added dropwise. The mixture was stirred at room temperature for 5 h,then a saturated aqueous solution of NaHCO₃ (15 mL) was added. Theseparated aqueous layer was extracted with DCM (2×20 mL). The combinedorganic layer was washed with brine, dried over Na₂SO₄ and concentratedunder reduced pressure. The residue was purified on C18 silica (120 gBiotage) using 50% B in A to 100% B (B=ACN 0.1% HCOOH, A=0.1% HCOOH) toprovide the title compound (10 mg, 35%) as a solid. M-kft: 1161.7.

Step 12

Benzyl((S)-1-((2S,5R,6R)-5-azido-6-(((1R,2R,3S,4R,6S)-4,6-diazido-2-(((2S,3R,4S,5R)-4-(((2R,3R,4R,5S,6S)-3-azido-6-(azidomethyl)-4,5-dihydroxytetrahydro-2H-pyran-2-yl)oxy)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)oxy)-3-hydroxycyclohexyl)oxy)tetrahydro-2H-pyran-2-yl)ethyl)(benzyl)carbamate

NaOMe (4.62 M in methanol, 0.01 mL, 0.06 mmol) was added dropwise to asolution of(2S,3R,4R,5R,6R)-6-(((2R,3R,4R,5S)-4-acetoxy-5-(((1S,2S,3R,5S,6R)-2-acetoxy-3,5-diazido-6-(((2R,3R,6S)-3-azido-6-((S)-1-(benzyl((benzyloxy)carbonyl)amino)ethyl)tetrahydro-2H-pyran-2-yl)oxy)cyclohexyl)oxy)-2-(acetoxymethyl)tetrahydrofuran-3-yl)oxy)-5-azido-2-(azidomethyl)tetrahydro-2H-pyran-3,4-diyldiacetate (9 mg, 0.01 mmol) in MeOH (5 mL) at room temperature. After 4h, AcOH (4 μL, 0.07 mmol) was added to the reaction and the mixture wasconcentrated under reduced pressure. The residue was purified byprep-HPLC using ACN and AmFor pH 4 to provide the title compound (9 mg,68%) as a solid. M-41⁺:951.4.

Step 13

(2S,3S,4R,5R,6R)-5-Amino-2-(aminomethyl)-6-(((2R,3S,4R,5S)-5-(((1R,2R,3S,5R,6S)-3,5-diamino-2-(((2R,3R,6S)-3-amino-6-((S)-1-aminoethyl)tetrahydro-2H-pyran-2-yl)oxy)-6-hydroxycyclohexyl)oxy)-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)tetrahydro-2H-pyran-3,4-diol

A mixture of benzyl((S)-1-((2S,5R,6R)-5-azido-6-(((1R,2R,3S,4R,6S)-4,6-diazido-2-(((2S,3R,4S,5R)-4-(((2R,3R,4R,5S,6S)-3-azido-6-(azidomethyl)-4,5-dihydroxytetrahydro-2H-pyran-2-yl)oxy)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)oxy)-3-hydroxycyclohexyl)oxy)tetrahydro-2H-pyran-2-yl)ethyl)(benzyl)carbamate(5 mg, 5 μmol) and Pd(OH)₂ (20% wt, 5 mg) in MeOH (8 mL) washydrogenated for 18 h at room temperature. The mixture was degassed withN₂ for 5 min, then filtered on 0.40 μM syringe filter. The solvent wasremoved under reduced pressure. The material was purified on prep-HPLCusing ACN and water (0.1%) formic acid to provide the title compound(1.5 mg, 32%) as the formate salt. M+H⁺: 597.3, ¹H NMR (400 MHz, CD₃OD)δ 8.51 (br, 6H), 5.87 (s, 1H), 5.36 (s, 1H), 5.25 (s, 1H), 4.50-4.42 (m,1H), 4.39-4.31 (m, 1H), 4.33-4.25 (m, 1H), 4.23-4.15 (m, 1H), 4.12 (s,1H), 4.00-3.91 (m, 1H), 3.91-3.82 (m, 1H), 3.75-3.61 (m, 3H), 3.54-3.33(m, 4H), 3.26-3.16 (m, 2H), 3.16-3.01 (m, 2H), 2.79-2.68 (m, 1H),2.28-2.17 (m, 1H), 2.08-1.89 (m, 3H), 1.64-1.41 (m, 2H), 1.29 (d, J=6.6Hz, 3H).

Example 3

Step 1

(NE)-N-[[(2S)-3,4-Dihydro-2H-pyran-2-yl]methylene]-2-methyl-propane-2-sulfinamide

(R)-(+)-2-Methyl-2-propanesulfinamide (81.1 g, 669 mmol) and CuSO₄(213.5 g, 1.34 mol) were mixed in DCM (700 mL). A solution of2-formyl-3,4-dihydro-2H-pyran (75 g, 669 mmol) in DCM (100 mL) was addedover 20 min. The mixture was stirred at room temperature for 72 h. Themixture was filtered through Celite and rinsed with DCM. The filtratewas evaporated under reduced pressure. The material was purified onsilica gel (5×330 g, dry loading) by MPLC using 0-10% Et2O in hexane toprovide the title compound (28 g, 19%) as a solid. ¹H NMR (400 MHz,CDCl₃) δ 8.07 (d, J=3.1 Hz, 1H), 6.40 (d, J=5.8 Hz, 1H), 4.76-4.68 (m,1H), 4.68-4.63 (m, 1H), 2.13-1.83 (m, 4H), 1.18 (s, 9H).

Step 2

N-[(1R)-1-[(2S)-3,4-Dihydro-2H-pyran-2-yl]ethyl]-2-methyl-propane-2-sulfinamide

MeMgBr (3.0 M in Et₂O, 22.0 mL, 66.0 mmol) was added to a solution of(NE)-N-[[(2S)-3,4-dihydro-2H-pyran-2-yl]methylene]-2-methyl-propane-2-sulfinamide(7.10 g, 33.0 mmol) in dry DCM (110 mL) at −40° C. under N₂. After 2 h,the reaction was warmed to room temperature within 1 h. After another 14h, sat. NH₄Cl (160 mL) was added dropwise (nota bene: gas evolution).Two phases were separated and the aqueous phase was extracted with DCM(3×20.0 mL). The combined organic layers were dried (Na₂SO₄), filteredand concentrated under reduced pressure. The residue was purified bysilica gel chromatography (220 g cartridge) with EtOAc and hexanes(20-45%) to provide the title compound as a solid (6.00 g, 79%). ¹H NMR(500 MHz, CDCl₃) δ 6.37 (d, J=6.1 Hz, 1H), 4.75-4.61 (m, 1H), 3.93 (ddd,J=11.2, 3.3, 2.0 Hz, 1H), 3.69 (d, J=6.1 Hz, 1H), 3.56 (pd, J=6.7, 3.5Hz, 1H), 2.16-2.06 (m, 1H), 1.99 (dtt, J=17.1, 5.6, 1.6 Hz, 1H), 1.81(ddd, J=13.3, 6.6, 1.8 Hz, 1H), 1.66 (dtd, J=13.3, 11.4, 5.8 Hz, 1H),1.22 (s, 9H), 1.18 (d, J=6.7 Hz, 3H).

Step 3

(R)—N-Benzyl-N-[(1R)-1-[(2S)-3,4-dihydro-2H-pyran-2-yl]ethyl]-2-methyl-propane-2-sulfinamide

NaH (60%, 187 mg, 4.89 mmol) was added to a mixture of(R)—N-[(1R)-1-[(2S)-3,4-dihydro-2H-pyran-2-yl]ethyl]-2-methyl-propane-2-sulfinamide(1.03 g, 4.44 mmol) and BnBr (0.79 mL, 6.67 mmol) in DMF (60 mL) at 0°C. The mixture was stirred at room temperature for 1 h, then brine (250mL) was added at 0° C. The aqueous layer was extracted with Et₂O (3×80mL). The combined organic layer was dried over MgSO₄ and concentratedunder reduced pressure. The material was purified on silica gel (40 g,dry loading) by MPLC using hexane to 60% EtOAc in hexane to provide thetitle compound (1.2 g, 84%) as an oil. ¹H NMR (400 MHz, cdcl3) δ 7.37(d, J=7.5 Hz, 2H), 7.32 (t, J=7.4 Hz, 2H), 7.26 (d, J=3.8 Hz, 1H), 6.32(d, J=6.2 Hz, 1H), 4.64 (s, 1H), 4.39 (d, J=15.3 Hz, 1H), 4.14 (d,J=15.2 Hz,1H), 3.66-3.57 (m, 1H), 3.32-3.20 (m, 1H), 1.98-1.80 (m, 3H),1.54-1.43 (m, 1H), 1.37 (d, J=6.8 Hz, 3H), 1.19 (s, 9H).

Step 4

(R)—N-Benzyl-N-[(1R)-1-[(2S)-6-hydroxy-5-iodo-tetrahydropyran-2-yl]ethyl]-2-methyl-propane-2-sulfinamide

I₂ (947 mg, 3.73 mmol) was added portionwise to a suspension of(R)—N-benzyl-N-[(1R)-1-[(2S)-3,4-dihydro-2H-pyran-2-yl]ethyl]-2-methyl-propane-2-sulfinamide(1.2 g, 3.73 mmol) and NaHCO₃ (941 mg, 11.2 mmol) in ACN (50 mL) and H₂O(50 mL) at 0° C. The mixture was stirred at room temperature for 1 h,then a saturated aqueous solution of Na₂S₂O₃ (10 mL) was added. Theaqueous layer was extracted with EtOAc (3×150 mL). The combined organiclayer was washed with brine, dried over MgSO₄, filtered and concentratedunder reduced pressure to provide the title compound (1.6 g, 92%) as asolid. M+H⁺: 466.1.

Step 5

BenzylN-benzyl-N-[(1R)-1-[(2S)-6-hydroxy-5-iodo-tetrahydropyran-2-yl]ethyl]carbamate

1N HCl (6.45 mL, 6.45 mmol) was added to a mixture of(R)—N-benzyl-N-[(1R)-1-[(2S)-6-hydroxy-5-iodo-tetrahydropyran-2-yl]ethyl]-2-methyl-propane-2-sulfinamide(1.2 g, 2.58 mmol) in dioxane (40 mL). The mixture was stirred at roomtemperature for 20 min, then Na₂CO₃ (2.19 g, 20.6 mmol) was added. After20 min, CbzCl (0.51 mL, 3.61 mmol) was added dropwise. The mixture wasstirred at room temperature for 2 h. Water (200 mL) was added. Theseparated aqueous layer was extracted with EtOAc (3×150 mL). Thecombined organic layer was washed with brine, dried over MgSO₄ andconcentrated under reduced pressure. The material was purified onsilical gel (80 g, dry loading) by MPLC using hexane to 80% EtOAc toprovide the title compound (1.1 g, 86%) as a solid. M+H⁺: 496.0.

Step 6

BenzylN-[(1R)-1-[(2S)-5-azido-6-oxo-tetrahydropyran-2-yl]ethyl]-N-benzyl-carbamate

Dess-Martin Periodinane (1.88 g, 4.44 mmol) was added to a solution ofbenzylN-benzyl-N-[(1R)-1-[(2S)-6-hydroxy-5-iodo-tetrahydropyran-2-yl]ethyl]carbamate(1.10 g, 2.22 mmol) in DCM (100 mL) at 0° C. The mixture was stirred atroom temperature for 5 h. Water (100 mL) was added following by asaturated aqueous solution of Na₂S₂O₃. The separated aqueous layer wasextract with DCM (2×50 mL). The combined organic layer were washed withsaturated aqueous NaHCO₃ (2×100 mL), brine (100 mL), dried over MgSO₄and concentrated under reduced pressure. The residue was taken inanhydrous DMF (75 mL) and NaN₃ (217 mg, 3.33 mmol) was added. Themixture was stirred at room temperature for 15 min, then brine (300 mL)was added. The aqueous layer was extracted with Et₂O (3×100 mL). Thecombined organic layers were dried over MgSO₄ and concentrated underreduced pressure. The material was purified on silica gel (40 g, dryloading) by MPLC using hexane to EtOAc to provide the title compound(800 mg, 88%) as an oil. M+H⁺: 409.3.

Step 7

BenzylN-[(1R)-1-[(2S)-5-azido-6-hydroxy-tetrahydropyran-2-yl]ethyl]-N-benzyl-carbamate

DIBAL-H (1 M in toluene, 11.8 mL, 11.8 mmol) was added dropwise to asolution of benzylN-[(1R)-1-[(2S)-5-azido-6-oxo-tetrahydropyran-2-yl]ethyl]-N-benzyl-carbamate(800 mg, 1.96 mmol) in DCM (60 mL) at −78° C. After 1 h at −78° C., EtOH(0.5 mL) was added dropwise. The mixture was poured into a saturatedaqueous solution of Rochelle's salt (300 mL). The mixture was vigorouslystirred for 1 h. The separated aqueous layer was extracted with DCM(2×75 mL). The combined organic layer was washed with brine, dried overMgSO₄ and concentrated under reduced pressure. The residue was purifiedon silica gel (40 g, dry loading) by MPLC using hexane to 60% EtOAc inhexane to provide the title compound (363 mg, 41%) as an oil. M+H⁺:411.2.

Step 8

[(1S,2S,3R,4S,6R)-2-Acetoxy-4,6-diazido-3-[(2R,6S)-3-azido-6-[(1R)-1-[benzyl(benzyloxycarbonyl)amino]ethyl]tetrahydropyran-2-yl]oxy-cyclohexyl]acetate

CCl₃CN (0.44 mL, 4.39 mol) was added dropwise to a suspension of benzylN-[(1R)-1-[(2S)-5-azido-6-hydroxy-tetrahydropyran-2-yl]ethyl]-N-benzyl-carbamate(360 mg, 0.88 mmol) and K₂CO₃ (364 mg, 2.63 mmol) in dry DCM (10 mL) atambient temperature under N₂. The mixture was stirred at roomtemperature for 8 h, then filtered on celite and rinsed with DCM. Thefiltrate was concentrated under reduced pressure. The residue was takenup in DCM (10 mL) and[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-hydroxy-cyclohexyl]acetate(654 mg, 2.19 mmol) was added. The mixture was cooled to −78° C., thenBF₃.OEt₂ (0.43 mL, 3.51 mmol) was added dropwise. The mixture wasstirred at room temperature for 5 h, then a saturated aqueous solutionof NaHCO₃ (50 mL) was added. The separated aqueous layer was extratecwith DCM (2×30 mL). The combined organic layer was washed with brine,dried over Na₂SO₄ and concentrated under reduced pressure. The residuewas purified on C18 silica (120 g Biotage) using 45% B in A to 100% B(B=ACN 0.1% HCOOH, A=0.1% HCOOH). The mixture of diastereoisomers wasused for the next step without further purification. M+H⁺: 691.3.

Step 9

BenzylN-[(1R)-1-[(2S,5S,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]ethyl]-N-benzyl-carbamate

NaOMe (4.62 M, 0.22 mL, 1.03 mmol) was added dropwise to a solution of[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-[(2R,3S,6S)-3-azido-6-(benzyloxycarbonylaminomethyl)tetrahydropyran-2-yl]oxy-cyclohexyl]acetate(118 mg, 0.171 mmol) in MeOH (8 mL) at room temperature. After 60 min,AcOH (0.08 mL, 1.37 mmol) was added to the reaction and the mixture wasconcentrated under reduced pressure. The material was purified by chiralSFC to yield 55 mg, 53%. M+H⁺: 607.4.

Step 10

[(1S,2S,3R,4S,6R)-4,6-Diazido-3-[(2R,3R,6S)-3-azido-6-[(1R)-1-[benzyl(benzyloxycarbonyl)amino]ethyl]tetrahydropyran-2-yl]oxy-2-hydroxy-cyclohexyl]acetate

Ac₂O (0.02 mL, 0.16 mmol) was added to a solution ofN-[(1R)-1-[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]ethyl]-N-benzyl-carbamate(55 mg, 0.09 mmol) and pyridine (0.05 mL, 0.54 mmol) in dry DCM (5 mL)at room temperature. After 22 h, MeOH (0.5 mL) was added and thevolatiles were removed under reduced pressure. The material was purifiedby prep-HPLC using ACN and AmFor (pH 4) to provide the title compound(32 mg, 54%) as a solid. M+H⁺: 649.3.

Step 11

(2S,3R,4R,5R,6R)-6-(((2R,3R,4R,5S)-4-Acetoxy-5-(((1S,2S,3R,5S,6R)-2-acetoxy-3,5-diazido-6-(((2S,3S,6R)-3-azido-6-((S)-1-(benzyl((benzyloxy)carbonyl)amino)ethyl)tetrahydro-2H-pyran-2-yl)oxy)cyclohexyl)oxy)-2-(acetoxymethyl)tetrahydrofuran-3-yl)oxy)-5-azido-2-(azidomethyl)tetrahydro-2H-pyran-3,4-diyldiacetate

CCl₃CN (0.07 mL, 0.67 mol) was added dropwise to a mixture of[(2R,3R,4R)-4-acetoxy-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-5-hydroxy-tetrahydrofuran-2-yl]methylacetate (71 mg, 0.13 mmol) and K₂CO₃ (56 mg, 0.40 mmol) in dry DCM (8mL) at room temperature under N₂. The mixture was stirred at roomtemperature for 18 h, then filtered with a filter syringe and rinsedwith DCM. The filtrate was concentrated under reduced pressure.

[(1S,2S,3R,4S,6R)-4,6-diazido-3-[(2R,3R,6S)-3-azido-6-[(1R)-1-[benzyl(benzyloxycarbonyl)amino]ethyl]tetrahydropyran-2-yl]oxy-2-hydroxy-cyclohexyl]acetate(29 mg, 0.045 mmol) was dissolved in DCM (8 mL) and added to theprevious reaction mixture. 4 Å molecular sieves were added and themixture was cooled to −78° C., then BF₃.OEt₂ (0.03 mL, 0.22 mmol) wasadded dropwise. The mixture was stirred at room temperature for 5 h,then a saturated aqueous solution of NaHCO₃ (15 mL) was added. Theseparated aqueous layer was extracted with DCM (2×20 mL). The combinedorganic layer was washed with brine, dried over Na₂SO₄ and concentratedunder reduced pressure. The residue was purified on C18 silica (120 gBiotage) using 50% B in A to 100% B (B=ACN 0.1% HCOOH, A=0.1% HCOOH) toprovide the title compound (35 mg, 67%) as a solid. M+H⁺: 1161.7.

Step 12

Benzyl((R)-1-((2S,5R,6R)-5-azido-6-(((1R,2R,3S,4R,6S)-4,6-diazido-2-(((2S,3R,4S,5R)-4-(((2R,3R,4R,5S,6S)-3-azido-6-(azidomethyl)-4,5-dihydroxytetrahydro-2H-pyran-2-yl)oxy)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)oxy)-3-hydroxycyclohexyl)oxy)tetrahydro-2H-pyran-2-yl)ethyl)(benzyl)carbamate

NaOMe (4.62 M, 0.05 mL, 0.24 mmol) was added dropwise to a solution of(2S,3R,4R,5R,6R)-6-(((2R,3R,4R,5S)-4-acetoxy-5-(((1S,2S,3R,5S,6R)-2-acetoxy-3,5-diazido-6-(((2S,3S,6R)-3-azido-6-((S)-1-(benzyl((benzyloxy)carbonyl)amino)ethyl)tetrahydro-2H-pyran-2-yl)oxy)cyclohexyl)oxy)-2-(acetoxymethyl)tetrahydrofuran-3-yl)oxy)-5-azido-2-(azidomethyl)tetrahydro-2H-pyran-3,4-diyldiacetate (35 mg, 0.03 mmol) in MeOH (5 mL) at room temperature. After 4h, AcOH (0.02 mL, 0.271 mmol) was added to the reaction and the mixturewas concentrated under reduced pressure. The residue was purified byprep-HPLC using ACN and AmFor pH 4 to provide the title compound (20 mg,70%) as a solid. M+H⁺: 951.3.

Step 13

(2S,3S,4R,5R,6R)-5-Amino-2-(aminomethyl)-6-(((2R,3S,4R,5S)-5-(((1R,2R,3S,5R,6S)-3,5-diamino-2-(((2R,3R,6S)-3-amino-6-((R)-1-aminoethyl)tetrahydro-2H-pyran-2-yl)oxy)-6-hydroxycyclohexyl)oxy)-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)tetrahydro-2H-pyran-3,4-diol

A mixture ofbenzyl((R)-1-((2S,5R,6R)-5-azido-6-4(1R,2R,3S,4R,6S)-4,6-diazido-2-(((2S,3R,4S,5R)-4-4(2R,3R,4R,5S,6S)-3-azido-6-(azidomethyl)-4,5-dihydroxytetrahydro-2H-pyran-2-yl)oxy)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)oxy)-3-hydroxycyclohexyl)oxy)tetrahydro-2H-pyran-2-yl)ethyl)(benzyl)carbamate(20 mg, 0.02 mmol) and Pd(OH)₂ (20% wt, 10 mg, 0.02 mmol) in MeOH (8 mL)was hydrogenated for 18 h at room temperature. The mixture was degassedwith N₂ for 5 min, then filtered on 0.40 μM syringe filter. The solventwas removed under reduced pressure to provide the title compound (8.5mg, 68%) as a solid. M+H⁺: 597.3 ¹H NMR (500 MHz, MeOD) δ 5.30 (d, J=3.4Hz, 1H), 5.23 (d, J=2.7 Hz, 1H), 4.88 (d, J=1.7 Hz, 1H), 4.32 (dd,J=6.0, 5.1 Hz, 1H), 4.14-4.11 (m, 1H), 4.03 (dt, J=6.4, 3.8 Hz, 1H),3.90-3.80 (m, 3H), 3.78-3.70 (m, 2H), 3.66 (dd, J=12.1, 4.3 Hz, 1H),3.50-3.45 (m, 1H), 3.45-3.43 (m, 1H), 3.35 (t, J=9.3 Hz, 1H), 3.11 (t,J=9.5 Hz, 1H), 3.00 (dd, J=13.2, 8.3 Hz, 1H), 2.97-2.90 (m, 2H),2.87-2.74 (m, 3H), 2.59 (ddd, J=12.1, 9.8, 4.1 Hz, 1H), 1.92 (dt,J=12.9, 4.1 Hz, 1H), 1.74-1.63 (m, 3H), 1.48-1.38 (m, 1H), 1.09 (d,J=6.2 Hz, 3H).

Example 4

Step 1

(S)—N-[(1S)-1-[(2S)-3,4-Dihydro-2H-pyran-2-yl]propyl]-2-methyl-propane-2-sulfinamide

EtMgBr (3.0 M in Et₂O, 9.29 mL, 27.9 mmol) was added to a solution of(NE,S)—N-[[(2S)-3,4-dihydro-2H-pyran-2-yl]methylene]-2-methyl-propane-2-sulfinamide(3.00 g,13.9 mmol) in dry THF (100.0 mL) at −78° C. under N₂. After 1 h,the reaction was stirred at −40° C. for 1 h and then warmed to roomtemperature within 1 h. After 1 h, the reaction was cooled to 0° C. andsat. NH₄Cl (100.0 mL) was added dropwise (nota bene: gas evolution). THFwas evaporated under reduced pressure and then the mixture was extractedwith EtOAc (3×100.0 mL). The combined organic layers were dried(Na₂SO₄), filtered and concentrated under reduced pressure to providethe title compound as a liquid. The crude was clean and used in the nextstep without further purification. LCMS m/z ES⁺ [M+Na]⁺: 268.20, LCMS(A05) retention time=1.65 and 1.70 m.

Step 2

(S)—N-benzyl-N-((S)-1-((S)-3,4-dihydro-2H-pyran-2-yl)propyl)-2-methylpropane-2-sulfinamide

A mixture of(S)—N-[(1S)-1-[(2S)-3,4-Dihydro-2H-pyran-2-yl]propyl]-2-methyl-propane-2-sulfinamide(2.97 g, 12.1 mmol), bromomethylbenzene (2.59 mL, 21.8 mmol) in DMF (65mL) was stirred at 0° C. NaH (0.581 g, 14.5 mmol) was then added to thereaction mixture portionwise. The mixture was allowed to stir at roomtemperature for 48 h. The reaction was quenched with water (200 mL) andthe mixture was extract with EtOAc (3×100 mL). The organic layers werecombined, washed with water and dried over sodium sulfate and thenconcentrated under reduced pressure. The residue was purified on silicagel (120 g) using hexane and ethyl acetate (70/30) as eluent to give thetitle product (2.74 g, 68%) as an oil. LCMS m/z ES⁺[M+Na]⁺: 358.14, LCMS(B05) retention time=2.41 m.

Step 3

(S)—N-benzyl-N-((1S)-1-((2S)-6-hydroxy-5-iodotetrahydro-2H-pyran-2-yl)propyl)-2-methylpropane-2-sulfinamide

Iodine (2.07 g, 8.17 mmol) was added portionwise to a suspension of(S)—N-benzyl-N—((S)-1-((S)-3,4-dihydro-2H-pyran-2-yl)propyl)-2-methylpropane-2-sulfinamide(2.74 g, 8.17 mmol) and NaHCO₃ (2.06 g, 24.5 mmol) in ACN (42.0 mL) andH₂O (42.0 mL) at 0° C. The mixture was stirred at 0° C. for 15 min.Then, the mixture was stirred at room temperature for 15 min. Aftercompletion, a saturated aqueous solution of Na₂S₂O₃ (200 mL) was added.The aqueous layer was extracted with EtOAc (3×100 mL). The combinedorganic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure to provide the title compound (3.92 g, 100%) as an oil.The crude was used in the next step without further purification. LCMSm/z ES⁺[M+Na]⁺: 502.04, LCMS (B05) retention time=2.51 m.

Step 4

Benzylbenzyl((1S)-1-((2S)-6-hydroxy-5-iodotetrahydro-2H-pyran-2-yl)propyl)carbamate

Aqueous HCl (1.0 M, 49.3 mL, 49.3 mmol) was dropwise added to a solutionof(S)—N-benzyl-N-((1S)-1-((2S)-6-hydroxy-5-iodotetrahydro-2H-pyran-2-yl)propyl)-2-methylpropane-2-sulfinamide(3.92 g, 8.18 mmol) in dioxane (100.0 mL) with vigorous stirring. After1 h, solid Na₂CO₃ (6.93 g, 65.4 mmol) was added. After another 10 min,CbzCl (1.97 mL, 13.8 mmol) was added dropwise. After another 30-45 min,dioxane was evaporated and the residue was partitioned in between EtOAc(150.0 mL) and H₂O (150.0 mL). The organic phase was dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude was purifiedby silica gel chromatography (120 g cartridge) using hexanes and ethylacetate (0-30%) as eluent to give the title product (diastereomers, 2.80g, 67%) as an oil. LCMS m/z ES⁺[M+Na]⁺: 532.90, LCMS (B05) retentiontime=2.41, 2.50, and 2.74 m.

Step 5

Benzylbenzyl((1S)-1-((2S)-5-iodo-6-oxotetrahydro-2H-pyran-2-yl)propyl)carbamate

Benzylbenzyl((1S)-1-((2S)-6-hydroxy-5-iodotetrahydro-2H-pyran-2-yl)propyl)carbamate(2.79 g, 5.48 mmol) was dissolved in DCM (120.0 mL). 4 Å molecularsieves (5.0 g) were suspended in the mixture, and PDC (6.18 g, 16.4mmol) was added. Stirring was continued over 24 hours at roomtemperature, then filtered through a silica pad using ethyl acetate aseluent. The filtrate was concentrated in vacuo to afford the titlecompound as an oil. The crude was used in the next step without furtherpurification. LCMS m/z: ES⁺[M+Na]⁺: 530.95; (B05) retention time=2.41 m.

Step 6

Benzyl((1S)-1-((2S)-5-azido-6-oxotetrahydro-2H-pyran-2-yl)propyl)(benzyl)carbamate

NaN₃ (0.413 mg, 6.36 mmol) was added to a solution of benzylbenzyl((1S)-1-((2S)-5-iodo-6-oxotetrahydro-2H-pyran-2-yl)propyl)carbamate(2.15 g, 4.24 mmol) in DMF (50.0 mL). The mixture was stirred for 2hours at 0° C. Water (100.0 mL) was added and the mixture was extractedwith EtOAc (3×50 mL). The organic layers were combined and then washedwith water (5×100 mL). The organic layer was dried over Na₂SO₄,concentrated in vacuo and purified by silica gel chromatography (80 gcartridge) to afford the title compound as an oil (1.30 g, 73%). LCMSm/z: ES⁺[M+Na]⁺: 445.96; (B05) retention time=2.16 m.

Step 7

Benzyl((1S)-1-((2S)-5-azido-6-hydroxytetrahydro-2H-pyran-2-yl)propyl)(benzyl)carbamate

DIBAL-H (1.00 M, 4.54 mL, 4.54 mmol) in DCM was added dropwise to asolution ofbenzyl((1S)-1-((2S)-5-azido-6-oxotetrahydro-2H-pyran-2-yl)propyl)(benzyl)carbamatein DCM (75.0 mL) at −78° C. under N₂. After 1 h, acetone (1.00 mL) wasadded to the reaction mixture dropwise. After 5 min, sat. potassiumsodium tartrate (100 mL) was added to the solution slowly, followed bythe addition of water (100 mL). The mixture was allowed to warm to roomtemperature and vigorously stirred overnight in the presence of ethylacetate. The organic layer was separated and the aqueous layer wasextracted with ethyl acetate (3×100 mL). The combined organic layerswere dried (Na₂SO₄), filtered and concentrated under reduced pressure toprovide the title compound as an oil (diastereomers, 1.10 g, 91%). Thismixture was used in the next step without further purification LCMS m/z:ES⁺[M+Na]⁺: 446.93; (B05) retention time=2.31 m.

Step 8

(1S,2S,3R,4S,6R)-4,6-diazido-3-(((2R,3R,6S)-3-azido-6-((S)-1-(benzyl((benzyloxy)carbonyl)amino)propyl)tetrahydro-2H-pyran-2-yl)oxy)cyclohexane-1,2-diyldiacetate

CCl₃CN (0.877 mL, 8.75 mmol) was added dropwise to a suspension ofbenzyl((1S)-1-((2S)-5-azido-6-hydroxytetrahydro-2H-pyran-2-yl)propyl)(benzyl)carbamate(0.734 g, 1.73 mmol) and K₂CO₃ (0.726 g, 5.25 mmol) in dry DCM (30.0 mL)at ambient temperature under N₂. After 12 h, the solution was filteredthrough Celite and the filtrate was concentrated by high-vacuum. To thecrude was added[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-hydroxy-cyclohexyl]acetate(0.418 g, 1.40 mmol) and ground 4 Å sieves (1.0 g) and the mixture wasdissolved in dry DCM (30.0 mL). The suspension was stirred at ambienttemperature for 25 min. The solution was cooled to 0° C. and BF₃.OEt₂(0.864 mL, 7.00 mmol) was added dropwise with vigorous stirring. Thesolution was warmed to ambient temperature and stirred for another 3hours. The reaction was quenched with sat. NaHCO₃ (50.0 mL). The mixturewas successively extracted with DCM (3×50.0 mL) and the combined organiclayer were dried (Na₂SO₄), filtered and concentrated under reducedpressure. The crude was purified by silica gel chromatography (40 gcartridge) with EtOAc and hexanes (0-30%) to produce the title compoundas an oil (2 diastereomers, 0.64 g, 65%). LCMS m/z: [M+Na]⁺: 727.13;(B05) retention time=2.61 m.

Step 9

BenzylN-[(1S)-1-[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]propyl]-N-benzyl-carbamate

NaOMe (4.62 M, 737 μL, 3.41 mmol) was added dropwise to a solution of(1S,2S,3R,4S,6R)-4,6-diazido-3-(((2R,3R,6S)-3-azido-6-((S)-1-(benzyl((benzyloxy)carbonyl)amino)propyl)tetrahydro-2H-pyran-2-yl)oxy)cyclohexane-1,2-diyldiacetate (0.40 g, 0.568 mmol) in MeOH (35.0 mL) at room temperature.After 60 min, the reaction was neutralized with AcOH (260 μL, 4.54mmol). Water (20.0 mL) was added and the mixture was extracted with DCM(3×30.0 mL). The organic layers were combined, dried over Na₂SO₄ andthen concentrated under reduced pressure to provide a mixture of twodiastereomers (0.280 g, 80%). ES⁺ [M+Na]⁺: 643.89; (B05) retentiontime=2.31 m. The desired isomer was separated on a Yamazen purificationsystem using hexane and EtOAc to provide the desired diastereoisomer(100 mg, 28%) as a solid. ES⁺ [M+Na]⁺: 643.89.

Step 10

[(1S,2S,3R,4S,6R)-4,6-Diazido-3-[(2R,3R)-3-azido-6-[(1S)-1-[benzyl(benzyloxycarbonyl)amino]propyl]tetrahydropyran-2-yl]oxy-2-hydroxy-cyclohexyl]acetate

Ac₂O (32.0 μL, 338 μmol) was added to a solution of benzylN-[(1S)-1-[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]propyl]-N-benzyl-carbamate(70.0 mg, 113 μmol) and pyridine (54.7 μL, 677 μmol) in dry DCM (2.00mL) at ambient temperature. After 18 h, all volatiles were removed underreduced pressure. The crude was purified by silica gel chromatography(25 g cartridge) with EtOAc and hexanes (5-40%) to produce the titlecompound as an oil (45.0 mg, 60%). LCMS m/z: ES⁺[M+Na]⁺: 685.75; (B05),retention time=2.56 m.

Step 11

(2S,3R,4R,5R,6R)-6-(((2R,3R,4R,5S)-4-Acetoxy-5-(((1S,2S,3R,5S,6R)-2-acetoxy-3,5-diazido-6-(((2S,3S,6R)-3-azido-6-((S)-1-(benzyl((benzyloxy)carbonyl)amino)ethyl)tetrahydro-2H-pyran-2-yl)oxy)cyclohexyl)oxy)-2-(acetoxymethyl)tetrahydrofuran-3-yl)oxy)-5-azido-2-(azidomethyl)tetrahydro-2H-pyran-3,4-diyldiacetate

CCl₃CN (97.6 μL, 973 μmol) was added dropwise to a mixture of[(2R,3R,4R)-4-acetoxy-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-5-hydroxy-tetrahydrofuran-2-yl]methylacetate (138 mg, 0.260 mmol) and K₂CO₃ (80.7 mg, 0.584 mmol) in dry DCM(8.00 mL) at room temperature under N₂. The mixture was stirred at roomtemperature for 16 h, then filtered through Celite and rinsed with DCM.The filtrate was concentrated under reduced pressure. The crude wasdissolved in DCM (8.00 mL) and added to[(1S,2S,3R,4S,6R)-4,6-diazido-3-[(2R,3R,6S)-3-azido-6-[(1S)-1-[benzyl(benzyloxycarbonyl)amino]propyl]tetrahydropyran-2-yl]oxy-2-hydroxy-cyclohexyl]acetate(43.0 mg, 64.9 μmol). 4 Å molecular sieves (200 mg) were added and themixture was cooled to −78° C., then BF₃.OEt₂ (40.0 μL, 324 μmol) wasadded dropwise. The mixture was stirred at room temperature for 5 h,then a saturated aqueous solution of NaHCO₃ (15.0 mL) was added. Theseparated aqueous layer was extracted with DCM (3×20.0 mL). The combinedorganic layer was washed with brine, dried over Na₂SO₄ and concentratedunder reduced pressure. The residue was purified by silica gelchromatography (25 g) using hexane and ethyl acetate (0-30%) to providethe title compound (45.0 mg, 46%) as a an oil. LCMS m/z ES⁺[M+H]⁺:1175.12, LCMS (B05) retention time=2.44 m.

Step 12

NaOMe (25 wt %, 103 μL, 357 μmol) was added dropwise to a solution ofthe compound of step 11 above (35.0 mg, 298 μmol) in MeOH (5.0 mL) atambient temperature. After 1 hour, the reaction mixture was neutralizedby HOAc (˜341 μL) and all volatiles were removed under reduced pressure.The crude was dissolved with EtOAc, filtered through Celite and thefiltrate was concentrated under reduced pressure to produce benzyl((S)-1-((2S,5R,6R)-5-azido-6-(((1R,2R,3S,4R,6S)-4,6-diazido-2-(((2S,3R,4S,5R)-4-(((2R,3R,4R,5S,6S)-3-azido-6-(azidomethyl)-4,5-dihydroxytetrahydro-2H-pyran-2-yl)oxy)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)oxy)-3-hydroxycyclohexyl)oxy)tetrahydro-2H-pyran-2-yl)propyl)(benzyl)carbamateas an oil (26.0 mg, 91%). LCMS m/z: ES⁺[M+Na]⁺: 987.29, (B05) retentiontime=2.28 m.

Step 13

(2S,3S,4R,5R,6R)-5-Amino-2-(aminomethyl)-6-(((2R,3S,4R,5S)-5-(((1R,2R,3S,5R,6S)-3,5-diamino-2-(((2R,3R,6S)-3-amino-6-((S)-1-aminopropyl)tetrahydro-2H-pyran-2-yl)oxy)-6-hydroxycyclohexyl)oxy)-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)tetrahydro-2H-pyran-3,4-diolhexaformate

In a 2 neck flask equipped with a reflux condenser were added benzyl((S)-1-((2S,5R,6R)-5-azido-6-(((1R,2R,3S,4R,6S)-4,6-diazido-2-(((2S,3R,4S,5R)-4-(((2R,3R,4R,5S,6S)-3-azido-6-(azidomethyl)-4,5-dihydroxytetrahydro-2H-pyran-2-yl)oxy)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)oxy)-3-hydroxycyclohexyl)oxy)tetrahydro-2H-pyran-2-yl)propyl)(benzyl)carbamate(26 mg, 0.033 mmol) and Pd/C (10% dry on carbon, 8.6 mg, 0.01 mmol)followed by anhydrous MeOH (4 mL). Nitrogen was bubbled for 5 min, thenammonium formate (15.3 mg, 0.24 mmol) was added. The mixture was heat at63° C. for 30 min under N₂, then cooled to room temperature with anice-bath. The mixture was filtered with a filter syringe andconcentrated under reduced pressure. The material was purified byprep-HPLC using 5% B in A to 100% B (A: Amfor pH 4, B: ACN) on C18Xbridge 30×150 mm to provide the title compound (8.9 mg, 37%) as asolid. M+H⁺: 611.3. ¹H NMR (500 MHz, MeOD) δ 8.51 (s, 6H), 5.74 (s, 1H),5.36 (s, 1H), 5.26 (s, 1H), 4.48 (s, 1H), 4.42-4.24 (m, 3H), 4.13-4.09(m, 2H), 3.96-3.76 (m, 2H), 3.76-3.61 (m, 3H), 3.42 (m, 5H), 3.13 (s,3H), 2.31-2.25 (m, 1H), 2.13-1.92 (m, 3H), 1.89-1.50 (m, 4H), 1.05 (t,J=7.4 Hz, 3H).

Example 5

Step 1

(R)—N-[(1R)-1-[(2S)-3,4-Dihydro-2H-pyran-2-yl]propyl]-2-methyl-propane-2-sulfinamide

EtMgBr (3.0 M in Et₂O, 9.29 mL, 27.9 mmol) was added to a solution of(NE)-N-[[(2S)-3,4-dihydro-2H-pyran-2-yl]methylene]-2-methyl-propane-2-sulfinamide(3.00 g, 13.9 mmol) in dry THF (75.0 mL) at −78° C. under N₂. After 1 h,the reaction was stirred at −40° C. for 1 h and then warmed to roomtemperature within 1 h. After 1 h, the reaction was cooled to 0° C. andsat. NH₄Cl (100.0 mL) was added dropwise (nota bene: gas evolution). THFwas evaporated under reduced pressure and the resulting mixture wasextracted with EtOAc (3×100.0 mL). The combined organic layers weredried (Na₂SO₄), filtered and concentrated under reduced pressure toprovide the title compound as a liquid. The crude was clean and used inthe next step without further purification. ¹H NMR (500 MHz, CDCl₃) δ6.35 (d, J=6.1 Hz, 1H), 4.72-4.54 (m, 1H), 4.03 (ddd, J=11.1, 3.3, 2.0Hz, 1H), 3.64 (d, J=8.0 Hz, 1H), 3.29-3.14 (m, 1H), 2.19-2.02 (m, 1H),2.01 -1.90 (m, 1H), 1.85-1.47 (m, 4H), 1.23 (s, 9H), 0.95 (t, J=7.4 Hz,3H). LCMS m/z ES⁺[M+Na]: 267.94, LCMS (A05) retention time=1.65 m.

Step 2

(R)—N-benzyl-N—((R)-1-((S)-3,4-dihydro-2H-pyran-2-yl)propyl)-2-methylpropane-2-sulfinamide

A mixture of(R)—N-[(1R)-1-[(2S)-3,4-Dihydro-2H-pyran-2-yl]propyl]-2-methyl-propane-2-sulfinamide(3.41 g, 13.9 mmol), bromomethylbenzene (4.28 g, 25.0 mmol) in DMF (50.0mL) was stirred at 0° C. NaH (0.667 g, 16.7 mmol) was then added to thereaction mixture portionwise. The mixture was allowed to stir at roomtemperature for 48 h. The reaction was quenched with water (100 mL) andthe mixture was extract with EtOAc (3×50 mL). The organic layers werecombined, dried over sodium sulfate and concentrated under reducedpressure. The residue was purified on silica gel (120 g) using hexaneand ethyl acetate (70/30) as eluent to give the title product (2.90 g,62%) as a colorless oil. LCMS m/z ES⁺[M+H]⁺: 335.94, LCMS (B05)retention time=2.12 m.

Step 3

N-Benzyl-N-[(1R)-1-[(2S)-6-hydroxy-5-iodo-tetrahydropyran-2-yl]propyl]-2-methyl-propane-2-sulfinamide

Iodine (2.33 g, 9.18 mmol) was added portionwise to a suspension of(R)-N-benzyl-N—((R)-1-((S)-3,4-dihydro-2H-pyran-2-yl)propyl)-2-methylpropane-2-sulfinamide(3.08 g, 9.18 mmol) and NaHCO₃ (2.31 g, 27.5 mmol) in ACN (53 mL) andH₂O (53 mL) at 0° C. The mixture was stirred at 0° C. for 15 min, thenthe mixture was stirred at room temperature for 15 min. Aftercompletion, a saturated aqueous solution of Na₂S₂O₃ (100 mL) was added.The aqueous layer was extracted with EtOAc (3×100 mL). The combinedorganic layer was dried over Na₂SO₄, filtered, concentrated underreduced pressure to provide the title compound (2.90 g, 66%) as a yellowsolid. The crude was used in the next step without further purification.LCMS m/z ES⁺[M+Na]⁺: 502.75, LCMS (B05) retention time=1.95 and 2.93 m.

Step 4

BenzylN-benzyl-N-[(1R)-1-[(2S)-6-hydroxy-5-iodo-tetrahydropyran-2-yl]propyl]carbamate

Aqueous HCl (1.0 M, 55.3 mL, 55.3 mmol) was dropwise added to a solutionofN-benzyl-N-[(1R)-1-[(2S)-6-hydroxy-5-iodo-tetrahydropyran-2-yl]propyl]-2-methyl-propane-2-sulfinamide(4.40 g, 9.18 mmol) in dioxane (130.0 mL) with vigorous stirring. After1 h, solid Na₂CO₃ (7.78 g, 73.4 mmol) was added. After another 10 min,CbzCl (2.21 mL, 15.5 mmol) was added dropwise. After another 30-45 min,dioxane was evaporated and the residue was partitioned in between EtOAc(100.0 mL) and H₂O (100.0 mL). The organic phase was dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude was purifiedby silica gel chromatography (120 g cartridge) using hexanes and ethylacetate (0-30%) as eluent to give the title product (diastereomers, 2.80g, 60%) as an oil. LCMS m/z ES⁺[M+Na]⁺: 531.89, LCMS (B05) retentiontime=2.10 and 2.15 m.

Step 5

BenzylN-benzyl-N-[(1R)-1-[(2S)-5-iodo-6-oxo-tetrahydropyran-2-yl]propyl]carbamate

BenzylN-benzyl-N-[(1R)-1-[(2S)-6-hydroxy-5-iodo-tetrahydropyran-2-yl]propyl]carbamate(2.80 g, 5.49 mmol) was dissolved in DCM (200.0 mL). 4 Å molecularsieves (2.0 g) were suspended in the mixture, and PDC (6.20 g, 16.4mmol) was added. Stirring was continued over 24 hours at roomtemperature, then the reaction was filtered through a Silica pad usingethyl acetate as eluent. The filtrate was concentrated in vacuo toafford the title compound as an oil. The crude was used in the next stepwithout further purification. LCMS m/z: ES⁺[M+H ]⁺: 507.94; (B05)retention time=2.12 m.

Step 6

BenzylN-[(1R)-1-[(2S)-5-azido-6-oxo-tetrahydropyran-2-yl]propyl]-N-benzyl-carbamate

NaN₃ (633 mg, 9.47 mmol) was added to a solution of benzylN-benzyl-N-[(1R)-1-[(2S)-5-iodo-6-oxo-tetrahydropyran-2-yl]propyl]carbamate(2.47 g, 4.87 mmol) in DMF (50.0 mL). The mixture was stirred for 2hours at room temperature. Water (100.0 mL) was added and the mixturewas extracted with EtOAc (3×50 mL). The organic layers were combined andthen washed with water (5×100 mL). The organic layer was dried overNa₂SO₄, concentrated in vacuo and purified by silica gel chromatography(80 g cartridge) to afford the title compound as an oil (0.825 g, 40%).LCMS m/z: ES⁺[M+Na ]⁺: 444.95; (B05) retention time=2.10-2.20 m.

Step 7

Benzyl((1R)-1-((2S)-5-azido-6-hydroxytetrahydro-2H-pyran-2-yl)propyl)(benzyl)carbamate

DIBAL-H (1 M, 2.94 mL, 2.94 mmol) in toluene was added dropwise to asolution of benzylN-[(1R)-1-[(2S)-5-azido-6-oxo-tetrahydropyran-2-yl]propyl]-N-benzyl-carbamate(0.777 g, 1.84 mmol) in dry DCM (50.0 mL) at −78° C. under N₂. After 1h, acetone (1.0 mL) was added to the reaction mixture dropwise. After 5min, sat. potassium sodium tartrate (100.0 mL) was added to the solutionslowly, followed by the addition of water (100.0 mL). The mixture wasallowed to warm to room temperature and vigorously stirred for overnightin the presence of ethyl acetate. The organic layer was separated andthe aqueous layer was extracted with ethyl acetate (3×100 mL). Thecombined organic layers were dried (Na₂SO₄), filtered and concentratedunder reduced pressure to provide the title compound as an oil(diastereomers, 0.75 g, 96%). This mixture was used in the next stepwithout further purification LCMS m/z: ES⁺ [M+Na]⁺: 447.91; (B05)retention time=2.10 m.

Step 8

(1S,2S,3R,4S,6R)-4,6-diazido-3-(((2R,6S)-3-azido-6-((R)-1-(benzyl((benzyloxy)carbonyl)amino)propyl)tetrahydro-2H-pyran-2-yl)oxy)cyclohexane-1,2-diyldiacetate

CCl₃CN (0.877 mL, 8.75 mmol) was added dropwise to a suspension ofbenzyl((1R)-1-((2S)-5-azido-6-hydroxytetrahydro-2H-pyran-2-yl)propyl)(benzyl)carbamate(0.767 g, 5.25 mmol) and K₂CO₃ (0.726 g, 5.25 mmol) in dry DCM (30.0 mL)at ambient temperature under N₂. After 12 h, the solution was filteredthrough Celite and the filtrate was concentrated by high-vacuum. To thecrude was added[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-hydroxy-cyclohexyl]acetate(0.418 g, 1.40 mmol) and ground 4 Å sieves (1.0 g) and the mixture wasdissolved in dry DCM (30.0 mL). The suspension was stirred at ambienttemperature for 25 min. The solution was cooled to 0° C. and BF₃.OEt₂(0.864 mL, 7.0 mmol) was added dropwise with vigorous stirring. Thesolution was warmed to ambient temperature and stirred for another 3hours. The reaction was quenched with sat. NaHCO₃ (50.0 mL). The mixturewas successively extracted with DCM (3×50 mL) and the combined organiclayer were dried (Na₂SO₄), filtered and concentrated under reducedpressure. The crude was purified by silica gel chromatography (40 gcartridge) with EtOAc and hexanes (0-30%) to produce the title compoundas an oil (2 diastereomers, 0.64 g, 65%). LCMS m/z: [M+Na]⁺: 727.60;(B05) retention time=2.37 m.

Step 9

Benzyl((R)-1-((2S,5R,6R)-5-azido-6-(((1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxycyclohexyl)oxy)tetrahydro-2H-pyran-2-yl)propyl)(benzyl)carbamate

NaOMe (4.62 M, 1.14 mL, 5.30 mmol) was added dropwise to a solution of(1S,2S,3R,4S,6R)-4,6-diazido-3-(((2R,6S)-3-azido-6-((R)-1-(benzyl((benzyloxy)carbonyl)amino)propyl)tetrahydro-2H-pyran-2-yl)oxy)cyclohexane-1,2-diyldiacetate (0.622 g, 0.883 mmol) in MeOH (30.0 mL) at room temperature.After 60 min, AcOH (0.404 mL, 7.06 mmol) was added to the reaction.Water (30.0 mL) was added and the mixture was extracted with DCM (3×50mL). The organic layers were combined, dried over Na₂SO₄ and thenconcentrated under reduced pressure to provide a mixture of twodiastereomers (0.450 g). The diastereoisomers were separated on Yamazenpurification system using hexane and EtOAc to provide the title desireddiastereoisomer (105 mg, 19%) as a solid. ES⁺[M+H]⁺: 621.15.

Step 10

(1S,2S,3R,4S,6R)-4,6-diazido-3-(((2R,3R,6S)-3-azido-6-((R)-1-(benzyl((benzyloxy)carbonyl)amino)propyl)tetrahydro-2H-pyran-2-yl)oxy)-2-hydroxycyclohexylacetate

Ac₂O (14.4 μL, 152 μmol) was added to a solution of benzyl((R)-1-((2S,5R,6R)-5-azido-6-(((1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxycyclohexyl)oxy)tetrahydro-2H-pyran-2-yl)propyl)(benzyl)carbamate(21.0 mg, 33.8 μmol) and pyridine (16.4 μL, 203 μmol) in dry DCM (2.0mL) at ambient temperature. After 48 h, all volatiles were removed underreduced pressure. The crude was purified by silica gel chromatography (4g cartridge) with EtOAc and hexanes (5-20%) to produce the titlecompound as an oil (16.0 mg, 71%). LCMS m/z: ES⁺[M+Na]⁺: 685.17; (B05)retention time=2.31 m.

Step 11

((2R,3S,4R,5S)-3-(((2R,3R,4R,5S,6S)-3-Azido-6-(azidomethyl)-4,5-dihydroxytetrahydro-2H-pyran-2-yl)oxy)-5-(((1R,2R,3S,5R,6S)-3,5-diazido-2-(((2R,3R,6S)-3-azido-6-((R)-1-(benzyl((benzyloxy)carbonyl)amino)propyl)tetrahydro-2H-pyran-2-yl)oxy)-6-hydroxycyclohexyl)oxy)-4-hydroxytetrahydrofuran-2-yl)methylacetate

CCl₃CN (70.4 μL, 702 μmol) was added dropwise to a mixture of[(2R,3R,4R)-4-acetoxy-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-5-hydroxy-tetrahydrofuran-2-yl]methylacetate (74.4 mg, 0.140 mmol) and K₂CO₃ (58.2 mg, 0.421 mmol) in dry DCM(8.0 mL) at room temperature under N₂. The mixture was stirred at roomtemperature for 18 h, then filtered through Celite and rinsed with DCM.The filtrate was concentrated under reduced pressure. The crude wasdissolved in DCM (8 mL) and added to(1S,2S,3R,4S,6R)-4,6-diazido-3-(((2R,3R,6S)-3-azido-6-((R)-1-(benzyl((benzyloxy)carbonyl)amino)propyl)tetrahydro-2H-pyran-2-yl)oxy)-2-hydroxycyclohexylacetate. 4 A molecular sieves (200 mg) were added and the mixture wascooled to −78° C., then BF₃.OEt₂ (28.9 μL, 234 μmol) was added dropwise.The mixture was stirred at room temperature for 5 h, then a saturatedaqueous solution of NaHCO₃ (15 mL) was added. The separated aqueouslayer was extracted with DCM (3×20 mL). The combined organic layer waswashed with brine, dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by silica gel chromatography (25 g)using hexane and ethyl acetate (0-30%) to provide the title compound(35.0 mg, 64%) as a an oil. LCMS m/z ES⁺[M+H]⁺: 1175.29, LCMS (B05)retention time=2.46 m.

Step 12

Benzyl((R)-1-((2S,5R,6R)-5-azido-6-(((1R,2R,3S,4R,6S)-4,6-diazido-2-(((2S,3R,4S,5R)-4-(((2R,3R,4R,5S,6S)-3-azido-6-(azidomethyl)-4,5-dihydroxytetrahydro-2H-pyran-2-yl)oxy)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)oxy)-3-hydroxycyclohexyl)oxy)tetrahydro-2H-pyran-2-yl)propyl)(benzyl)carbamate

NaOMe (25 wt %, 106 μL, 368 μmol) was added dropwise to a solution ofcompound((2R,3S,4R,5S)-3-(((2R,3R,4R,5S,6S)-3-Azido-6-(azidomethyl)-4,5-dihydroxytetrahydro-2H-pyran-2-yl)oxy)-5-(((1R,2R,3S,5R,6S)-3,5-diazido-2-(((2R,3R,6S)-3-azido-6-((R)-1-(benzyl((benzyloxy)carbonyl)amino)propyl)tetrahydro-2H-pyran-2-yl)oxy)-6-hydroxycyclohexyl)oxy)-4-hydroxytetrahydrofuran-2-yl)methylacetate (36.0 mg, 306 μmol) in MeOH (3.0 mL) at ambient temperature.After 1 hour, the reaction mixture was neutralized by HOAc (˜35 μL) andall volatiles were removed under reduced pressure. The crude wasdissolved with EtOAc, filtered and the filtrate was concentrated underreduced pressure to produce the title compound as an oil (29.6 mg,100%). LCMS m/z: ES⁺[M+Na]⁺: 987.19, (B05) retention time=2.19 m.

Step 13

(2S,3S,4R,5R,6R)-5-Amino-2-(aminomethyl)-6-(((2R,3S,4R,5S)-5-(((1R,2R,3S,5R,6S)-3,5-diamino-2-(((2R,3R,6S)-3-amino-6-((R)-1-aminopropyl)tetrahydro-2H-pyran-2-yl)oxy)-6-hydroxycyclohexyl)oxy)-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)tetrahydro-2H-pyran-3,4-diolhexaformate

In a 2 neck flask equipped with a reflux condenser were added benzyl((R)-1-((2S,5R,6R)-5-azido-6-(((1R,2R,3S,4R,6S)-4,6-diazido-2-(((2S,3R,4S,5R)-4-(((2R,3R,4R,5S,6S)-3-azido-6-(azidomethyl)-4,5-dihydroxytetrahydro-2H-pyran-2-yl)oxy)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)oxy)-3-hydroxycyclohexyl)oxy)tetrahydro-2H-pyran-2-yl)propyl)(benzyl)carbamate(27 mg, 0.03 mmol) and Pd/C (10% dry on carbon, 8.9 mg, 0.01 mmol)following by anhydrous MeOH (4 mL). Nitrogen was bubbled for 5 min, thenammonium formate was added. The mixture was heated at 63° C. for 30 minunder N₂, then cooled to room temperature with an ice-bath. The mixturewas filtered with a filter syringe and concentrated under reducedpressure. The material was purified by prep-HPLC using 5% B in A to 100%B (A: Amfor pH 4, B: ACN) on C18 Xbridge 30×150 mm to provide the titlecompound (7.9 mg, 46%) as a solid. M+H⁺: 611.3. ¹H NMR(400 MHz, D₂O) δ8.58 (s, 6H), 6.03 (d, J=3.6 Hz, 1H), 5.55 (d, J=2.6 Hz, 1H), 5.45 (s,1H),4.67-4.61 (m, 1H), 4.53 (dd, J=4.8, 2.8 Hz, 1H), 4.47 (t, J=5.1 Hz,1H), 4.38 (s, 2H), 4.25 (d, J=12.2Hz, 1H), 4.16 (t, J=9.6 Hz, 1H),4.10-4.00 (m, 2H), 3.98 (d, J=1.5 Hz, 1H), 3.92-3.80 (m, 2H), 3.74 (s,1H), 3.72-3.43 (m, 6H), 2.62 (dd, J=8.4, 4.3 Hz, 1H), 2.26-1.94 (m, 4H),1.91 -1.60 (m, 3H), 1.14 (t, J=7.5 Hz, 3H).

Example 6

(1S,2R,3R,4S,6R)-4,6-Diamino-3-[(2R,3R,6S)-3-amino-6-[(1S)-1-aminopropyl]tetrahydropyran-2-yl]oxy-cyclohexane-1,2-diol

Pd(OH)₂/C (20 wt %, 136 mg, 193 μmol) was added to a solution of benzylN-[(1S)-1-[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]propyl]-N-benzyl-carbamate(made in Example 4, 30.0 mg, 48.3 μmol) in MeOH (2.50 mL) and EtOH (2.50mL). H₂ was bubbled through the suspension. After 16 h, the solution wasfiltered through a frit (0.22 μm diameter) and the filtrate wasconcentrated under reduced pressure to give the desired product as anoil which turn into solid after lyophilization (12.1 mg, 77%). ¹H NMR(500 MHz, MeOD) δ 5.40 (d, J=3.5 Hz, 1H), 4.14-4.07 (m, 1H), 3.47 (t,J=9.1 Hz, 1H),3.36 (t, J=9.4 Hz, 1H), 3.23 (t, J=9.5 Hz, 1H), 3.13-3.07(m, 1H), 3.07-3.00 (m, 1H), 2.97-2.83 (m,2H), 2.17-2.08 (m, 1H),1.92-1.66 (m, 5H), 1.63-1.50 (m, 2H), 1.06 (t, J=7.5 Hz, 3H).

Example 7

(1S,2R,3R,4S,6R)-4,6-Diamino-3-[(2R,3R,6S)-3-amino-6-[(1R)-1-aminoethyl]tetrahydropyran-2-yl]oxy-cyclohexane-1,2-diol

Pd(OH)₂/C (20 wt %, 119 mg, 169 μmol) was added to a solution of benzylN-[(1R)-1-[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]propyl]-N-benzyl-carbamate(made in Example 5, 35.0 mg, 56.4 μmol) in MeOH (2.5 mL) and EtOH (2.5mL). H₂ was bubbled through the suspension. After 17 h, the solution wasfiltered through a frit (0.22 μm diameter) and the filtrate wasconcentrated under reduced pressure to give the desired product as anoil which turn into solid after lyophilization (14.3 mg, 80%). ¹H NMR(500 MHz, MeOD) δ 5.23 (d, J=3.5 Hz, 1H), 4.01-3.92 (m, 1H), 3.43 (t,J=9.1 Hz, 1H), 3.27 (t, J=9.3 Hz, 1H), 3.13 (t, J=9.4 Hz, 1H), 2.98 2.80(m, 3H), 2.79 2.66 (m, 1H), 2.06 (dt, J=12.8, 4.2 Hz, 1H), 1.89 1.45 (m,7H), 1.04 (t, J=7.5 Hz, 3H).

Example 8

Step 1

(1S,2R,3R,4S,6R)-4,6-Diazido-3-[(2R,3S,4R,5R,6R)-3-azido-6-(azidomethyl)-5-benzyloxy-4-fluoro-tetrahydropyran-2-yl]oxy-cyclohexane-1,2-diol

(2R,3R,4R,5R,6R)-5-azido-2-(azidomethyl)-3-benzyloxy-4-fluoro-6-(p-tolylsulfanyl)tetrahydropyran(preparation below, 385 mg, 0.898 mmol) and[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-hydroxy-cyclohexyl]acetate(255 mg, 0.855 mmol) were coevaporated with dry toluene 3 times andfurther dried under high vacuum. Anhydrous Et₂O (8 mL) and DCM (4 mL)were added followed by preactivated 4 Å molecular sieves. After stirringfor 30 min at room temperature, the mixture was cooled to −40° C. MS(500 mg, 2.22 mmol) was added and the reaction mixture was stirred for20 min at −40° C. TfOH (0.04 mL, 0.427 mmol) was added, and the reactionwas warmed to −20° C. and kept stirring for 30 min. Sodium bisulfite(200 mg), NaHCO₃ (200 mg), and water (10 mL) were added at 0° C., andthe mixture was stirred for 10 min at room temperature. The reactionmixture was diluted with DCM (50 mL), filtered through a Celite pad, andwashed with a saturated solution of aqueous NaHCO₃ (60 mL). The aqueouslayers were extracted with DCM (50 mL×3), and the combined organic phasewas washed with brine, dried over MgSO₄, filtered, and concentratedunder reduced pressure. The residue was taken up in dry MeOH (25 mL) andNaOMe (4.62 M in MeOH, 0.56 mL, 2.56 mmol) was added. The mixture wasstirred at room temperature for 1 h. Water (50 mL) was added. Theaqueous layer was extracted with DCM (3×50 mL). The combined organiclayer was washed with brine, dried over MgSO₄ and concentrated underreduced pressure. The material was purified on silica gel (40 g, dryloading) by MPLC using 0% to 50% EtOAc in hexane to provide the titlecompound (96 mg, 22% over 2 steps). ¹H NMR (400 MHz, CDCl₃) δ 7.45-7.27(m, 5H), 5.25 5.18 (m, 1H), 5.10-4.86 (m, 2H), 4.67-4.59 (m, 1H),4.15-4.08 (m, 1H), 3.90-3.84 (m, 1H), 3.83-3.65 (m, 2H), 3.62-3.53 (m,1H), 3.52-3.35 (m, 3H), 3.28-3.21 (m, 1H), 2.76 (s, 1H), 2.36-2.24 (m,1H), 1.25 (t, J=12.0 Hz, 3H).

Step 2

[(1S,2S,3R,4S,6R)-4,6-diazido-3-[(2R,3S,4R,5R,6R)-3-Azido-6-(azidomethyl)-5-benzyloxy-4-fluoro-tetrahydropyran-2-yl]oxy-2-hydroxy-cyclohexyl]acetate

Ac₂O (9 μL, 95 μmol) was added to a solution of(1S,2R,3R,4S,6R)-4,6-diazido-3-[(2R,3S,4R,5R,6R)-3-azido-6-(azidomethyl)-5-benzyloxy-4-fluoro-tetrahydropyran-2-yl]oxy-cyclohexane-1,2-diol(24 mg, 46 μmol) and pyridine (23 μL, 278 μmol) in dry DCM (0.80 mL) atambient temperature. After 20 h, all volatiles were removed underreduced pressure. The crude was purified by silica gel chromatography (4g cartridge) with EtOAc and hexanes (5-20%) to produce the titlecompound as an oil (21 mg, 81%). ¹H NMR (500 MHz, CDCl₃) δ 7.43 7.28 (m,5H), 5.25 (t, J=3.7 Hz, 1H), 5.10-4.85 (m, 3H), 4.63 (d, J=11.0 Hz, 1H),4.14-4.09 (m, 1H), 3.73 (dddd, J=13.3, 11.1, 9.7, 5.7 Hz, 3H), 3.62 (td,J=9.8, 2.4 Hz, 1H), 3.57 (dt, J=13.2, 2.1 Hz, 1H), 3.54-3.44 (m, 2H),3.38-3.32 (m, 1H), 3.27 (ddd, J=12.2, 10.0, 4.5 Hz, 1H), 2.36 (dt,J=13.3, 4.5 Hz, 1H), 2.17 (s, 3H), 1.58 (dd, J=25.7, 12.5 Hz, 1H).

Step 3

[(2R,3R,4R,5S)-4-Acetoxy-5-[(1S,2S,3R,5S,6R)-2-acetoxy-3,5-diazido-6-[(2R,3S,4R,5R,6R)-3-azido-6-(azidomethyl)-5-benzyloxy-4-fluoro-tetrahydropyran-2-yl]oxy-cyclohexoxy]-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-tetrahydrofuran-2-yl]methylacetate

CCl₃CN (38 μL, 375 μmol) was added dropwise to a suspension of[(2R,3R,4R)-4-acetoxy-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-5-hydroxy-tetrahydrofuran-2-yl]methylacetate (40 mg, 75 μmol) and K₂CO₃ (31 mg, 225 μmol) in dry DCM (1.50mL) at ambient temperature under N₂. After 15 h, the solution wasfiltered through cotton and the filtrate was concentrated under N₂stream, followed by high-vacuum. To the crude was added[(1S,2S,3R,4S,6R)-4,6-diazido-3-[(2R,3S,4R,5R,6R)-3-Azido-6-(azidomethyl)-5-benzyloxy-4-fluoro-tetrahydropyran-2-yl]oxy-2-hydroxy-cyclohexyl]acetate(21 mg, 38 μmol) in DCM (3.0 mL) and all volatiles were evaporated underN₂ stream. To the mixture was added ground 4 Å sieves (500 mg) and themixture was dissolved in dry DCM (1.0 mL). The suspension was stirred atambient temperature for 1 h. The solution was cooled to 0° C. andBF₃.OEt₂ (37 μL, 300 μmol) was added. The reaction mixture was warmed toroom temperature, stirred for 30 min followed by the addition of Et₃N(80 μL). The crude was filtered through a silica gel pad (0.30 g) withEtOAc (5.0 mL) and all volatiles were removed under reduced pressure.The crude was purified by C18 reversed phase chromatography (40 gcartridge) with ACN and 0.1% aq. formic acid (50-100%) to produce thetitle compound as a solid (20 mg, 60%). LCMS m/z: ES⁺[M+NH4]⁺: 1090.32;(A50) retention time=2.03 m.

Step 4

(2S,3S,4R,5R,6R)-5-Azido-2-(azidomethyl)-6-[(2R,3S,4R,5S)-5-[(1R,2R,3S,5R,6S)-3,5-diazido-2-[(2R,3S,4R,5R,6R)-3-azido-6-(azidomethyl)-5-benzyloxy-4-fluoro-tetrahydropyran-2-yl]oxy-6-hydroxy-cyclohexoxy]-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl]oxy-tetrahydropyran-3,4-diol

NaOMe (25 wt %, 45 μL, 157 μmol) was added dropwise to a solution of[(2R,3R,4R,5S)-4-acetoxy-5-[(1S,2S,3R,5S,6R)-2-acetoxy-3,5-diazido-6-[(2R,3S,4R,5R,6R)-3-azido-6-(azidomethyl)-5-benzyloxy-4-fluoro-tetrahydropyran-2-yl]oxy-cyclohexoxy]-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-tetrahydrofuran-2-yl]methylacetate (14 mg, 13 μmol) in MeOH (0.80 mL) at ambient temperature. After50 min, HOAc (15 μL) was added and all volatiles were removed underreduced pressure. The crude was filtered through a silica gel pad (0.20g) with EtOAc (6.0 mL) and the filtrate was concentrated under reducedpressure. The crude solid was washed with hexanes (3×1.0 mL) and thesupernatant was decanted to produce the title compound as a solid (10mg, 89%). ¹H NMR (400 MHz, cdcl3) δ 7.41-7.29 (m, 5H), 5.70 (t, J=3.5Hz, 1H), 5.37 (d, J=3.1 Hz, 1H), 5.11 (s, 1H), 5.10-4.93 (m, 1H), 4.91(d, J=11.2 Hz, 1H), 4.63 (d, J=11.2 Hz, 1H), 4.45 (t, J=5.1 Hz, 1H),4.29-4.17 (m, 3H), 4.11 (t, J=3.4 Hz, 1H), 4.05 (ddd, J=8.9, 3.7, 1.7Hz, 1H), 3.94-3.76 (m, 3H), 3.76-3.52 (m, 6H), 3.50-3.32 (m, 7H),3.13-3.00 (m, 2H), 2.28 (dt, J=13.1, 4.2 Hz, 1H), 1.75 (s, 1H), 1.47 (q,J=12.8 Hz, 1H). LCMS m/z: ES⁺[M+NH4]⁺: 880.37; (A05) retention time=2.54m.

Step 5

(2S,3S,4R,5R,6R)-5-Amino-2-(aminomethyl)-6-(((2R,3S,4R,5S)-5-(((1R,2R,3S,5R,6S)-3,5-diamino-2-(((2R,3S,4R,5R,6R)-3-amino-6-(aminomethyl)-4-fluoro-5-hydroxytetrahydro-2H-pyran-2-yl)oxy)-6-hydroxycyclohexyl)oxy)-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)tetrahydro-2H-pyran-3,4-diolhexakis(2,2,3,3,4,4,4-heptafluorobutanoate)

Pd(OH)₂/C (10 wt %, 60 mg, 43 μmol) was added to a solution of(2S,3S,4R,5R,6R)-5-azido-2-(azidomethyl)-6-[(2R,3S,4R,5S)-5-[(1R,2R,3S,5R,6S)-3,5-diazido-2-[(2R,3S,4R,5R,6R)-3-azido-6-(azidomethyl)-5-benzyloxy-4-fluoro-tetrahydropyran-2-yl]oxy-6-hydroxy-cyclohexoxy]-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl]oxy-tetrahydropyran-3,4-diol(20 mg, 23 μmol) in MeOH/AcOH (2:1, 3.0 mL) under N2 at ambienttemperature in a test tube. The tube was then placed in a hydrogenationbottle and kept agitated for 42 h under H₂ (50 psi). The material wasfiltered through a frit (0.55 μm diameter) and the filtrate wasconcentrated under reduced pressure. The compound was purified by aHFBA-Coupled prep-HPLC to provide the title compound as a solid(hexa-HFBA salt, 2.2 mg, 5%). ¹H NMR (500 MHz, MeOD) δ 6.11 (s, 1H),5.47 (s, 1H), 5.31 (s, 1H), 4.52 (t, J=5.9 Hz, 1H), 4.38-4.18 (m, 4H),4.14 (s, 1H), 4.00 (s, 1H), 3.93-3.84 (m, 2H), 3.81-3.56 (m, 6H),3.56-3.41 (m, 5H), 3.19-3.09 (m, 2H), 2.50 2.37 (m, 1H), 2.22-1.98 (m,2H).

Preparation of(2R,3R,4R,5R,6R)-5-azido-2-(azidomethyl)-3-benzyloxy-4-fluoro-6-(p-tolylsulfanyl)tetrahydropyran

Step 1(4aR,6S,7R,8R,8aR)-7-azido-8-fluoro-2-phenyl-6-(p-tolylthio)hexahydropyrano[3,2-d][1,3]dioxine

To a solution of 3.1 g of(4aR,6S,7R,8S,8aS)-7-azido-2-phenyl-6-(p-tolylthio)hexahydropyrano[3,2-d][1,3]dioxin-8-olin 30 mL of anhydrous DCM was added 6.3 mL of pyridine and the mixturewas cooled to 0° C. To this solution, 6.6 mL of triflic anhydride wasadded slowly and the reaction was stirred for 1 hour at the sametemperature. After completion, the organic layer was diluted with DCMand washed with 1N HCl and saturated NaHCO₃. The organic layer was driedover anhydrous sodium sulfate and concentrated. The obtained crude wasdissolved in 20 mL of tBuOH and 3.53 g of CsF was added and the reactionstirred at 50° C. until completion. The organic layer was diluted withEtOAc and washed with saturated NaHCO₃ and brine, then dried, filteredand concentrated. The crude was purified by flash chromatography toobtain 1.1 g of (4aR,6 S,7R, 8R,8aR)-7-azido-8-fluoro-2-phenyl-6-(p-tolylthio)hexahydropyrano[3,2-d][1,3]dioxine (35% yield).

Step 2((2R,3R,4R,5R,6S)-5-azido-3-(benzyloxy)-4-fluoro-6-(p-tolylthio)tetrahydro-2H-pyran-2-yl)methanol

To the solution of 100 mg of(4aR,6S,7R,8R,8aR)-7-azido-8-fluoro-2-phenyl-6-(p-tolylthio)hexahydropyrano[3,2-d][1,3]dioxinein 5 mL of anhydrous dichloromethane was added 4 A MS and the mixturewas stirred for 30 min at room temperature. The solution was cooled to−78° C. and 100 μL of triethyl silane and 84 μL of PhBCl₂ addedsuccessively and stirred at the same temperature until completion (20min). The reaction was quenched methanol (0.2 mL) and triethyl amine(0.2 mL). The reaction was diluted with DCM and filtered. The filtratewas washed with aqueous sodium bicarbonate and the organic layer wasdried, filtered and concentrated. The crude residue was purified byflash column chromatography (30% EtOAc in Hexanes) to afford 87 mg of((2R,3R,4R,5R,6S)-5-azido-3-(benzyloxy)-4-fluoro-6-(p-tolylthio)tetrahydro-2H-pyran-2-yl)methanol(90% yield).

Step 3(2S,3R,4R,5R,6R)-3-azido-6-(azidomethyl)-5-(benzyloxy)-4-fluoro-2-(p-tolylthio)tetrahydro-2H-pyran

To a solution of 850 mg of((2R,3R,4R,5R,6S)-5-azido-3-(benzyloxy)-4-fluoro-6-(p-tolylthio)tetrahydro-2H-pyran-2-yl)methanolin anhydrous DCM was added 1.7 mL of Pyridine and 800 mg of tosylchloride was added at 0° C. The reaction was stirred at the sametemperature until completion (3 h). The reaction was diluted with 100 mLof DCM and washed with 1N HCl and aq NaHCO₃, then dried, filtered andconcentrated. The crude was dissolved in 10 mL of anhydrous DMF and 750mg of sodium azide was added. The reaction was stirred at 70° C. untilcompletion. DMF was evaporated and the crude was dissolved in EtOAc andwashed with water. The organic layer was dried with MgSO₄, filtered,concentrated and purified by flash chromatography to afford 700 mg of(2S,3R,4R,5R,6R)-3-azido-6-(azidomethyl)-5-(benzyloxy)-4-fluoro-2-(p-tolylthio)tetrahydro-2H-pyran(83% yield).

Example 9

Step 1

(R)—N-[(R)-Cyclopropyl-[(2S)-3,4-dihydro-2H-pyran-2-yl]methyl]-2-methyl-propane-2-sulfinamide

Cyclopropyl MgBr (0.5 M in THF , 9.28 mL, 4.64 mmol) was added to asolution of(NE)-N-[[(2S)-3,4-dihydro-2H-pyran-2-yl]methylene]-2-methyl-propane-2-sulfinamide(500 mg, 2.32 mmol) in dry THF (15.0 mL) at −78° C. under N₂. After 1 h,the reaction was stirred at −40° C. for 1 h and then warmed to roomtemperature within 1 h. After 1 h, the reaction was cooled to 0° C. andsat. NH₄Cl (20.0 mL) was added dropwise (nota bene: gas evolution). Themixture was extracted with DCM (3×15.0 mL). The combined organic layerswere dried (Na₂SO₄), filtered and concentrated under reduced pressure toprovide the title compound as a liquid. The ¹H NMR for crude was cleanand used in the next step without further purification. ¹H NMR (400 MHz,CDCl₃) δ 6.37 (d, J=5.8 Hz, 1H), 4.68 (t, J=4.9 Hz, 1H), 4.13-3.95 (m,1H), 3.89-3.67 (m, 1H), 2.79-2.63 (m, 1H), 2.24-1.85 (m, 4H), 1.22 (s,9H), 0.93-0.79 (m, 1H), 0.69 -0.51 (m, 2H), 0.42-0.28 (m, 1H), 0.34-0.19(m, 1H). LCMS m/z ES⁺[M+H]: 258.19, LCMS (B05) retention time=1.7 m.

Step 2

(R)—N-Benzyl-N—[(R)-cyclopropyl(3,4-dihydro-2H-pyran-2-yl)methyl]-2-methyl-propane-2-sulfinamide

A mixture of(R)—N—[(R)-cyclopropyl(3,4-dihydro-2H-pyran-2-yl)methyl]-2-methyl-propane-2-sulfinamide(0.598 g, 2.32 mmol), bromomethylbenzene (0.596 g, 3.48 mmol) in DMF (10mL) was stirred at 0° C. NaH (92.8 mg, 2.32 mmol) was then added to thereaction mixture portionwise. The mixture was allowed to stir at roomtemperature for 24 h. The reaction was quenched with water and themixture was extract with EtOAc (3×15 mL). The organic layers werecombined, dried over sodium sulfate and concentrated under reducedpressure. The residue was purified on silica gel (24 g) using hexane andethyl acetate (70/30) as eluent to give the title product as a colorlessoil (473 mg, 59%). LCMS m/z ES⁺[M+H]⁺: 348.20, LCMS (B05) retentiontime=2.17 m. Major isomer: ¹H NMR (500 MHz, CDCl₃) δ 7.46-7.20 (m, 5H),6.47 (d, J=5.5 Hz, 1H), 4.73 (t, J=5.6 Hz, 1H), 4.59 (d, J=15.0 Hz, 1H),4.37 (d, J=14.9 Hz, 1H), 4.04 (d, J=10.7 Hz, 1H), 2.58 (d, J=8.2 Hz,1H), 2.14-2.02 (m, 1H), 1.96-1.93 (m, 2H), 1.72 (dd, J=12.6, 5.7 Hz,1H), 1.33-1.20 (m, 1H), 1.12 (s, 9H), 0.71 (ddd, J=14.9, 8.1, 4.3 Hz,1H), 0.64-0.51 (m, 1H), 0.37-0.25 (m, 1H).

Step 3

(R)—N-Benzyl-N—[(R)-cyclopropyl-[(2S)-6-hydroxy-5-iodo-tetrahydropyran-2-yl]methyl]-2-methyl-propane-2-sulfinamide

Iodine (1.79 g, 7.07 mmol) was added portionwise to a suspension of(R)—N-benzyl-N—[(R)-cyclopropyl-[(2S)-3,4-dihydro-2H-pyran-2-yl]methyl]-2-methyl-propane-2-sulfinamide(2.46 g, 7.07 mmol) and NaHCO₃ (1.78 g, 21.2 mmol) in ACN (43 mL) andH₂O (43 mL) at 0° C. The mixture was stirred at 0° C. for 15 min. Then,the mixture was stirred at room temperature for 15 min. Aftercompletion, a saturated aqueous solution of Na₂S₂O₃ (100 mL) was added.The aqueous layer was extracted with EtOAc (3×100 mL). The combinedorganic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure to provide the title compound (3.40 g, 97%) as a yellowsolid. The crude was used in the next step without further purification.LCMS m/z ES⁺ [M+Na]⁺: 514.50, LCMS (B05) retention time=1.98 and 2.07 m.

Step 4

BenzylN-benzyl-N-[(R)-cyclopropyl-[(2S)-6-hydroxy-5-iodo-tetrahydropyran-2-yl]methyl]carbamate

Aqueous HCl (1.0 M, 43.6 mL, 43.6 mmol) was dropwise added to a solutionof(R)—N—[(R)-[(2S)-5-azido-6-hydroxy-tetrahydropyran-2-yl]-cyclopropyl-methyl]-N-benzyl-2-methyl-propane-2-sulfinamide(3.56 g, 7.24 mmol) in dioxane (100.0 mL) with vigorous stirring. After1 h, solid Na₂CO₃ (6.14 g, 57.9 mmol) was added. After another 10 min,CbzCl (1.74 mL, 12.2 mmol) was added dropwise. After another 30-45 min,dioxane was evaporated and the residue was partitioned in between EtOAc(100 mL) and H₂O (100 mL). The organic phase was dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude was purifiedby silica gel chromatography (80 g cartridge) with EtOAc and hexanes(0-35%) to produce the title compound (mixture of 4 diastereomers) as anoil (2.78 g, 74%). LCMS m/z: ES⁺[M+Na]⁺: 544.01; (B05) retentiontime=2.15, 2.16, and 2.21 m.

Step 5

BenzylN-[(R)-[(2S)-5-azido-6-hydroxy-tetrahydropyran-2-yl]-cyclopropyl-methyl]-N-benzyl-carbamate

NaN₃ (1.04 g, 16.0 mmol) and K₂CO₃ (2.21 g, 16.0 mmol) was added to asolution of benzylN-benzyl-N-[(R)-cyclopropyl-[(2S)-6-hydroxy-5-iodo-tetrahydropyran-2-yl]methyl]carbamate(2.78 g, 5.33 mmol) in dry DMF (30.0 mL) under N₂ at ambienttemperature. After 4 h, the reaction was quenched with water (100.0 mL)and extracted with EtOAc (3×100.0 mL). The organic layer was dried overNa₂SO₄, filtered and concentrated under reduced pressure. The crude waspurified by silica gel chromatography (120 g cartridge) with EtOAc andhexanes (0-30%) to produce the title compound (diastereomers) as an oil(1.63 g, 70%). ES⁺[M+Na]⁺: 459.01; (B05) retention time=2.11 and 2.17 m.

Step 6

[(1S,2S,3R,4S,6R)-2-Acetoxy-4,6-diazido-3-[(2R,3R,6S)-3-azido-6-[(R)-[benzyl(benzyloxycarbonyl)amino]-cyclopropyl-methyl]tetrahydropyran-2-yl]oxy-cyclohexyl]acetate

CCl₃CN (0.940 mL, 9.38 mmol) was added dropwise to a suspension ofbenzylN—[(R)-[(2S)-5-azido-6-hydroxy-tetrahydropyran-2-yl]-cyclopropyl-methyl]-N-benzyl-carbamate(0.845 g, 1.94 mmol) and K₂CO₃ (0.777 g, 5.63 mmol) in dry DCM (30.0 mL)at ambient temperature under N₂. After 12 h, the solution was filteredthrough Celite and the filtrate was concentrated by high-vacuum. To thecrude was added[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-hydroxy-cyclohexyl]acetate(0.447 mg, 1.50 mmol) and ground 4 Å sieves (1.0 g) and the mixture wasdissolved in dry DCM (30.0 mL). The suspension was stirred at ambienttemperature for 30 min. The solution was cooled to 0° C. and BF₃.OEt₂(0.926 mL, 7.50 mmol) was added dropwise with vigorous stirring. Thesolution was warmed to ambient temperature and stirred for another 2hours. The reaction was quenched with sat. NaHCO₃ (50.0 mL). The mixturewas successively extracted with DCM (3×50 mL) and the combined organiclayer were dried (Na₂SO₄), filtered and concentrated under reducedpressure. The crude was purified by silica gel chromatography (80 gcartridge) with EtOAc and hexanes (5-30%) to produce the title compoundas an oil (2 diastereomers, 0.510 g, 47%). LCMS m/z: [M+Na]⁺: 739.19;(B05) retention time=2.39 m.

Step 7

BenzylN-[(R)-[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]-cyclopropyl-methyl]-N-benzyl-carbamate

NaOMe (4.62 M, 281.0 μL, 1.29 mmol) was added dropwise to a solution of[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-[(2R,6S)-3-azido-6-[(R)-[benzyl(benzyloxycarbonyl)amino]-cyclopropyl-methyl]tetrahydropyran-2-yl]oxy-cyclohexyl]acetate(155 mg, 0.216 mmol) in MeOH (10.0 mL) at room temperature. After 60min, AcOH (98.9 μL, 1.73 mmol) was added to the reaction and the mixturewas concentrated under reduced pressure to provide a mixture of twodiastereomers. ES⁺[M+Na]⁺:655.09; (B05) retention time=2.23 m. Themixture was purified by SFC. The ratio by SFC was found to be 1:7 infavor of the undesired isomer. Retention time of the undesired compoundis 4.69 min. Retention time of the desired compound is 7.48. 10 mg(7.3%) of the desired compound was isolated by SFC. 65 mg of theundesired compound was isolated by SFC.

Step 8

(1S,2R,3R,4S,6R)-4,6-diamino-3-(((2R,3R,6S)-3-amino-6-((R)-amino(cyclopropyl)methyl)tetrahydro-2H-pyran-2-yl)oxy)cyclohexane-1,2-diol

Pd(OH)₂/C (20 wt %, 102 mg, 145 μmol) was added to a solution of benzylN—[(R)-[(2S,5S,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]-cyclopropyl-methyl]-N-benzyl-carbamate(23.0 mg, 36.4 μmol) in MeOH (2.0 mL) and EtOH (2.0 mL). H₂ was bubbledthrough the suspension. After 24 h, the solution was filtered through afrit (0.22 μm diameter) and the filtrate was concentrated under reducedpressure to give the desired product as an oil which turn into solidafter lyophilization (10.5 mg, 87%). ¹H NMR (500 MHz, MeOD) δ 5.33 (d,J=3.6 Hz,1H), 4.10 -4.02 (m, 1H), 3.45 (t, J=9.1 Hz, 1H), 3.30 (t, J=9.3Hz, 1H), 3.13 (t, J=9.4 Hz, 1H), 2.98 -2.82 (m, 2H), 2.73 (ddd, J=12.2,9.8, 4.2 Hz, 1H), 2.53-2.41 (m, 1H), 2.27 (dd, J=9.9, 3.6 Hz, 1H), 2.05(dt, J=11.8, 4.1 Hz, 1H), 1.90-1.73 (m, 4H), 1.04-0.90 (m, 1H),0.74-0.56 (m, 2H), 0.42-0.30 (m, 2H).

Example 10

Step 1

(R)—N-[(1R)-1-[(2S)-6-Hydroxy-5-iodo-tetrahydropyran-2-yl]ethyl]-2-methyl-propane-2-sulfinamide

Iodine (339 mg, 1.34 mmol) was added to a suspension of(R)—N-[(1R)-1-[(2S)-3,4-dihydro-2H-pyran-2-yl]ethyl]-2-methyl-propane-2-sulfinamide(303 mg, 1.31 mmol) and NaHCO₃ (330 mg, 3.93 mmol) in 1:1 H₂O/ACN (6.0mL) at ambient temperature. After 30 min, acetonitrile was evaporatedand the remaining solution was partitioned in EtOAc (25.0 mL) and water(10.0 mL). The organic layer was separated, washed with brine (10.0 mL),dried (Na₂SO₄) and filtered under reduced pressure to provide the titlecompounds (2 diastereomers) as a wax (490 mg, 95%). LCMS m/z: ES⁺[M+H]⁺: 376.10; (A05) retention time=2.09 m. (A05) retention time=2.19m. This material was used in the following reactions without furtherpurifications.

Step 2

(R)—N-[(1R)-1-[(2S)-5-Iodo-6-oxo-tetrahydropyran-2-yl]ethyl]-2-methyl-propane-2-sulfinamide

Dess-Martin Periodinane (631 mg, 1.48 mmol) was added to a solution of(R)—N-[(1R)-1-[(2S)-6-hydroxy-5-iodo-tetrahydropyran-2-yl]ethyl]-2-methyl-propane-2-sulfinamide(490 mg, 1.24 mmol) in DCM (15.0 mL) at ambient temperature. After 16 h,DCM was evaporated under reduced pressure and the residue was partitionin between EtOAc (20.0 mL) and 1:1 sat. NaHCO₃/Na₂S₂O₃ (20.0 mL). Theorganic phase was successively washed with sat. NaHCO3 (10.0 mL) andbrine (10.0 mL), dried (Na₂SO₄), filtered and concentrated under reducedpressure to provide the title compound as an oil (463 mg, 100%). LCMSm/z: ES⁺[M+H]⁺: 374.08; (A05) retention time=2.03 m.

Step 3

(R)—N-[(1R)-1-[(2S)-5-Azido-6-oxo-tetrahydropyran-2-yl]ethyl]-2-methyl-propane-2-sulfinamide

NaN₃ (282 mg, 4.34 mmol) was added to a solution of(R)—N-[(1R)-1-[(2S)-5-iodo-6-oxo-tetrahydropyran-2-yl]ethyl]-2-methyl-propane-2-sulfinamide(463 mg, 1.24 mmol) in dry DMF (4.0 mL) at ambient temperature under N₂.After 16 h, the solution was filtered through a silica gel plug (4.0 g)with EtOAc (50.0 mL) and the filtrate was concentrated under reducedpressure. The crude was purified by silica gel chromatography (25 gcartridge) with EtOAc and hexanes (30%-70%) to provide the titlecompound as an oil (2 diastereomers, 100 mg, 28%). LCMS m/z: ES⁺ [M+H]⁺:289.25; (A05) retention time=1.98-2.01 m.

Step 4

(R)—N-[(1R)-1-[(2S)-5-Azido-6-hydroxy-tetrahydropyran-2-yl]ethyl]-2-methyl-propane-2-sulfinamide

DIBAL-H (1 M, 520 μL, 520 μmol) in toluene was dropwise added to asolution of(R)—N-[(1R)-1-[(2S)-5-azido-6-oxo-tetrahydropyran-2-yl]ethyl]-2-methyl-propane-2-sulfinamide(100 mg, 347 μmol) in dry DCM (4.5 mL) at −78° C. under N₂. After 1 h,acetone (100 μL) was added to the reaction mixture dropwise. After 5min, sat. potassium sodium tartrate (10.0 mL) was added to the solutionslowly, followed by the addition of water (10.0 mL). The mixture wasallowed to warmed to room temperature and vigorously stirred for 1 h.The mixture was extracted with DCM (15.0+3×5.0 mL). The combined organiclayers were dried (Na₂SO₄), filtered and concentrated under reducedpressure to provide the title compound as an oil (diastereomers, 80 mg,79%). LCMS m/z: ES⁺[M+H]⁺: 291.19; (A05) retention time=2.00 and 2.07 m.This material was used without further purifications.

Step 5

BenzylN-[(1R)-1-[(2S)-5-azido-6-hydroxy-tetrahydropyran-2-yl]ethyl]carbamate

Aqueous HCl (1.0 M, 1.37 mL, 1.37 mmol) was added dropwise to a solutionof(R)—N-[(1R)-1-[(2S)-5-azido-6-hydroxy-tetrahydropyran-2-yl]ethyl]-2-methyl-propane-2-sulfinamide(80 mg, 275 μmol) in dioxane (2.0 mL) with vigorous stirring. After 1 h,solid Na₂CO₃ (234 mg, 2.20 mmol) was added. After another 15 min, CbzCl(55 μL, 386 mmol) was added dropwise. After another 3 h, dioxane wasevaporated and the residue was partitioned in between EtOAc (20.0 mL)and H₂O (20.0 mL). The organic phase was washed with brine (10.0 mL),dried (Na₂SO₄), filtered and concentrated under reduced pressure. Thecrude was purified by silica gel chromatography (4 g cartridge) withEtOAc and hexanes (10-35%) to produce the title compound (mixture of 4diastereomers) as a solid (58 mg, 66%). LCMS m/z: ES⁺[M+H]⁺: 321.33;(A05) retention time=2.21, 2.24, 2.27, and 2.30 m.

Step 6

[(1S,2S,3R,4S,6R)-2-Acetoxy-4,6-diazido-3-[(2R,3R,6S)-3-azido-6-[(1R)-1-(benzyloxycarbonylamino)ethyl]tetrahydropyran-2-yl]oxy-cyclohexyl]acetate

CCl₃CN (91 μL, 905 μmol) was added dropwise to a suspension of benzylN-[(1R)-1-[(2S)-5-azido-6-hydroxy-tetrahydropyran-2-yl]ethyl]carbamate(58 mg, 181 μmol) and K₂CO₃ (75 mg, 543 μmol) in dry DCM (1.0 mL) atambient temperature under N₂. After 64 h, the solution was filteredthrough cotton and the filtrate was concentrated under N₂ stream,followed by high-vacuum treatment. To the crude (96 mg) was added[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-hydroxy-cyclohexyl]acetate (76mg, 253 μmol) and ground 4 Å sieves (220 mg) and the mixture wasdissolved in dry DCM (1.0 mL). The suspension was stirred at ambienttemperature for 30 min. The solution was cooled to 0° C. and BF₃.OEt₂(89 μL, 724 μmol) was added dropwise with vigorous stirring. Thesolution was warmed to ambient temperature and stirred for another 15min. The solution was cooled to 0° C. and sat. NaHCO₃ (5.0 mL) wasadded. After another 15 min, the mixture was successively extracted withDCM (3×5.0 mL) and the combined organic layers were dried (Na₂SO₄),filtered and concentrated under reduced pressure. The crude was purifiedby silica gel chromatography (12 g cartridge) with EtOAc and hexanes(5-30%) to produce[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-[(2R,3S,6S)-3-azido-6-[(1R)-1-(benzyloxycarbonylamino)ethyl]tetrahydropyran-2-yl]oxy-cyclohexyl]acetateas a solid (21 mg, 19%). ¹H NMR (500 MHz, CDCl₃) δ 7.37-7.28 (m, 5H),5.21 (d, J=8.6 Hz, 1H), 5.10 (t, J=13.1 Hz, 2H), 5.05-5.00 (m, 1H), 4.92(t, J=10.0 Hz, 1H), 4.88 (s, 1H), 4.05 (d, J=11.8 Hz, 1H), 3.77 (s, 1H),3.61 (t, J=9.7 Hz, 1H), 3.54 (ddd, J=12.6, 10.0, 4.6 Hz, 1H), 3.44 (ddd,J=12.4, 9.9, 4.5 Hz, 1H), 3.35 (d, J=1.5 Hz, 1H), 2.28 (dt, J=12.9, 4.0Hz, 1H), 2.07 (s, 6H), 2.05 -1.96 (m, 1H), 1.84 (dd, J=14.3, 3.2 Hz,1H),1.73-1.62 (m, 1H), 1.51 -1.38 (m, 2H), 1.17 (d, J=6.8 Hz, 3H).

Step 7

BenzylN-[(1R)-1-[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]ethyl]carbamate

NaOMe (25 wt %, 245 μL, 849 μmol) was added dropwise to a solution of[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-[(2R,3R,6S)-3-azido-6-[(1R)-1-(benzyloxycarbonylamino)ethyl]tetrahydropyran-2-yl]oxy-cyclohexyl]acetate(85 mg, 142 μmol) in MeOH (3.0 mL) at ambient temperature. After 90 min,HOAc (245 μL, 2.55 mmol) was added to the reaction mixture dropwise andall volatiles were removed under reduced pressure. The crude waspurified by silica gel chromatography (12 g cartridge) with EtOAc andhexanes (20-40%) to produce the title compound as a solid (26 mg, 36%).¹H NMR (500 MHz, Acetone) δ 7.44-7.23 (m, 5H), 6.25 (d, J=8.6 Hz, 1H),5.81-5.72 (m, 1H), 5.13-4.98 (m, 2H), 4.05 (ddd, J=11.9, 5.6, 2.1 Hz,1H), 3.73-3.65 (m, 1H), 3.65-3.57 (m, 3H), 3.57-3.51 (m, 1H), 3.44-3.32(m, 1H), 3.15 (dt, J=12.6, 4.1 Hz, 1H), 2.25 (dt, J=13.0, 4.2 Hz, 1H),2.14-2.06 (m, 1H), 1.92-1.82 (m, 2H), 1.53 (ddt, J=10.4, 7.6, 4.0 Hz,1H), 1.44-1.34 (m, 1H), 1.34-1.23 (m, 2H), 1.17 (d, J=6.8 Hz, 3H). LCMSm/z: ES⁺[M+H]⁺: 517.18; (A05) retention time=2.42 m.

Step 8

(1S,2R,3R,4S,6R)-4,6-Diamino-3-[(2R,3R,6S)-3-amino-6-[(1R)-1-aminoethyl]tetrahydropyran-2-yl]oxy-cyclohexane-1,2-diol

Pd(OH)₂/C (10 wt %, 7.5 mg, 5.4 μmol) was added to a solution of benzylN-[(1R)-1-[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]ethyl]carbamate(11 mg, 21.3 μmol) in EtOH/MeOH (1:1, 3.0 mL) under N₂ at ambienttemperature. H₂ was bubbled through the suspension for 10 min. After 17h, the solution was filtered through a frit (0.22 μm diameter) and thefiltrate was concentrated under reduced pressure, then lyophilized toprovide the title compound as a solid (8.2 mg, quantitative). ¹H NMR(500 MHz, MeOD) δ 5.12 (d, J=3.6 Hz, 1H), 3.74 (ddd, J=12.0, 4.3, 2.1Hz, 1H), 3.37 (t, J=9.1 Hz, 1H), 3.19 (t, J=9.2 Hz, 1H), 3.05 (t, J=9.4Hz, 1H), 2.95 -2.87 (m, 1H), 2.84-2.73 (m, 2H), 2.64 (ddd, J=12.0, 9.6,4.1 Hz, 1H), 1.99 (dt, J=12.9, 4.1 Hz, 1H), 1.80 -1.74 (m, 1H),1.74-1.63 (m, 2H), 1.52-1.41 (m, 1H), 1.21 (dd, J=25.0, 12.2 Hz, 1H),1.10 (d, J=6.7 Hz, 3H).

Example 11

Step 1

(R)—N-[[(2S)-3,4-Dihydro-2H-pyran-2-yl]methyl]-2-methyl-propane-2-sulfinamide

NaBH₄ (101 mg,2.66 mmol) was added to a solution of(NE)-N-[[(2S)-3,4-dihydro-2H-pyran-2-yl]methylene]-2-methyl-propane-2-sulfinamide(572 mg, 2.66 mmol) in reagent alcohol (10.0 mL) at 0° C. Ice bath wasremoved and the reaction was kept stirring for another 30 min. Thereaction was cooled to 0° C. and sat. NH₄Cl (20.0 mL) was added (notabene: gas evolution). EtOH was evaporated under reduced pressure and theresidue was extracted with EtOAc (30.0 mL). The layers were separatedand the organic phase was successively washed with water (10.0 mL) andbrine (10.0 mL), dried (Na₂SO₄), filtered and concentrated under reducedpressure to provide the title compound as a solid (547 mg, 95%). LCMSm/z: ES⁺[M+H]⁺: 218.20; (A05) retention time=2.04 m. This material wasused in the following steps without further purifications.

Step 2

(R)—N-Benzyl-N-[[(2S)-3,4-dihydro-2H-pyran-2-yl]methyl]-2-methyl-propane-2-sulfinamide

NaH (60%, 116 mg, 2.89 mmol) was added to a mixture of(R)-N-[[(2S)-3,4-dihydro-2H-pyran-2-yl]methyl]-2-methyl-propane-2-sulfinamide(547 mg, 2.52 mmol) and BnBr (448 μL, 3.78 mmol) in DMF (1.5 mL) at 0°C. The mixture was stirred at room temperature for 1 h, then cooled to0° C. followed by addition of water (10.0 mL). The aqueous layer wasextracted with EtOAc (25.0 mL) and the organic layer was successivelywashed with water (10.0 mL) and brine (5.0 mL), dried (Na₂SO₄), filteredand concentrated under reduced pressure. The crude was purified bysilica gel chromatography (24 g cartridge) with EtOAc and hexanes(0-40%) to produce the title compound as an oil (768 mg, 99%). LCMS m/z:ES⁺[M+H]⁺: 308.18; (A05) retention time=2.57 m.

Step 3

(R)—N-Benzyl-N-[(1R)-1-[(25)-6-hydroxy-5-iodo-tetrahydropyran-2-yl]ethyl]-2-methyl-propane-2-sulfinamide

Iodine (272 mg, 1.07 mmol) was added to a suspension of(R)—N-benzyl-N-[(1R)-1-[(2S)-3,4-dihydro-2H-pyran-2-yl]ethyl]-2-methyl-propane-2-sulfinamide(320 mg, 1.04 mmol) and NaHCO₃ (262 mg, 3.12 mmol) in 1:1 H₂O/ACN (8.0mL) at ambient temperature. After 30 min, MeCN was evaporated and theresidue was partitioned in between EtOAc (20.0 mL) and 1:1 sat.NaHCO₃/sat. Na₂S₂O₃ (10.0 mL). The organic layer was washed with water(5.0 mL) and brine (5.0 mL), dried (Na₂SO₄), filtered and concentratedunder reduced pressure to provide the title compound as a foam (4diastereomers, 450 mg, 96%). LCMS m/z: ES⁺[M+H]⁺: 452.06; (A05)retention time=2.30-2.50 m. This material was used in the followingreactions without further purifications.

Step 4

(R)—N-[[(2S)-5-Azido-6-oxo-tetrahydropyran-2-yl]methyl]-N-benzyl-2-methyl-propane-2-sulfinamide

4 Å Sieves (500 mg) and PDC (750 mg, 1.99 mmol) was added to a solutionof benzyl(R)—N-benzyl-N-[[(2S)-6-hydroxy-5-iodo-tetrahydropyran-2-yl]methyl]-2-methyl-propane-2-sulfinamide(450 mg, 997 μmol) in dry DCM (10.0 mL) under N₂ at ambient temperature.After 24 h, the solution was concentrated and the crude was partitionedin between EtOAc (30.0 mL) and water (15.0 mL). The organic layer waswashed with water (2×10.0 mL) and brine (10.0 mL), dried (Na₂SO₄) andconcentrated. The crude was dissolved in dry DMF (1.5 mL) under N₂ andNaN₃ (130 mg, 1.99 mmol) was added. After 1 h, the solution waspartitioned in between EtOAc (30.0 mL) and water (15.0 mL). The organiclayer was washed with water (2×10.0 mL) and brine (10.0 mL), dried(Na₂SO₄) and concentrated to provide the title compound as an oil (235mg, 64%). LCMS m/z: ES⁺[M+H]⁺: 365.17; (A05) retention time=2.37 m. Thismaterial was used in the next reactions without further purifications.

Step 5

(R)—N-[[(2S)-5-Azido-6-hydroxy-tetrahydropyran-2-yl]methyl]-N-benzyl-2-methyl-propane-2-sulfinamide

DIBAL-H (1 M, 1.03 mL, 1.03 mmol) in toluene was dropwise added to asolution of(R)—N-[[(2S)-5-azido-6-oxo-tetrahydropyran-2-yl]methyl]-N-benzyl-2-methyl-propane-2-sulfinamide(235 mg, 645 μmol) in dry DCM (8.0 mL) at −78° C. under N₂. After 100min, sat. potassium sodium tartrate (15.0 mL) was added to the solutionslowly, followed by the addition of water (15.0 mL). The mixture wasallowed to warm to room temperature and vigorously stirred for 16 h. Themixture was extracted with DCM (10.0+2×5.0 mL). The combined organiclayers were dried (Na₂SO₄), filtered and concentrated under reducedpressure. The crude was purified by silica gel chromatography (12 gcartridge) with EtOAc and hexanes (10%-50%) to provide the titlecompound as an oil (diastereomers, 195 mg, 74%). LCMS m/z: ES⁺[M+H]⁺:367.19; (A05) retention time=2.28-2.40 m.

Step 6

BenzylN-[[(2S)-5-azido-6-hydroxy-tetrahydropyran-2-yl]methyl]-N-benzyl-carbamate

Aqueous HCl (1.0 M, 2.66 mL, 2.66 mmol) was dropwise added to a solutionof(R)—N-[[(2S)-5-azido-6-hydroxy-tetrahydropyran-2-yl]methyl]-N-benzyl-2-methyl-propane-2-sulfinamide(195 mg, 532 μmol) in dioxane (2.7 mL) with vigorous stirring. After 1h, solid Na₂CO₃ (451 mg, 4.26 mmol) was added. After another 5 min,CbzCl (106 μL, 745 mmol) was added dropwise. After another 1 h, dioxanewas evaporated and the residue was partitioned in between EtOAc (20.0mL) and H₂O (20.0 mL). The organic phase was washed with brine (10.0mL), dried (Na₂SO₄), filtered and concentrated under reduced pressure.The crude was purified by C18 reverse phase chromatography (80 gcartridge) with ACN and 0.1% aq. formic acid (40-70%) to produce thetitle compound (mixture of 4 diastereomers) as an oil (167 mg, 79%).UPLC m/z: ES⁺[M-OH]⁺: 379.21; (CSH 5 to 100% ACN/AmFor pH 4) retentiontime=2.12, 2.15, 2.20, and 2.22 m. A portion (40 mg) of the material waspurified by prep-HPLC (CSH C18 ACN/AmForm 50-70%) to provide the a-azidoas a film (20 mg, 50% recovery). UPLC m/z: (CSH 5 to 100% ACN/AmFor pH4) retention time=2.15 and 2.22 m.

Step 7

[(1S,2S,3R,4S,6R)-2-Acetoxy-4,6-diazido-3-[(2R,6S)-3-azido-6-[[benzyl(benzyloxycarbonyl)amino]methyl]tetrahydropyran-2-yl]oxy-cyclohexyl]acetate

CCl₃CN (145 μL, 1.44 mmol) was added dropwise to a suspension of benzylN-[[(2S)-5-azido-6-hydroxy-tetrahydropyran-2-yl]methyl]-N-benzyl-carbamate(127 mg, 288 μmol) and K₂CO₃ (120 mg, 865 μmol) in dry DCM (2.0 mL) atambient temperature under N₂. After 20 h, the solution was filteredthrough cotton and the filtrate was concentrated under N₂ stream,followed by high-vacuum. To the crude (92 mg) was added[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-hydroxy-cyclohexyl]acetate(120 mg, 404 μmol) and ground 4 Å sieves (500 mg) and the mixture wasdissolved in dry DCM (2.0 mL). The suspension was stirred at ambienttemperature for 1 h. The solution was cooled to 0° C. and BF₃.OEt₂ (142μL, 1.15 mmol) was added dropwise with vigorous stirring. The solutionwas warmed to ambient temperature and stirred for another 15 min. Thereaction was quenched with sat. NaHCO₃ (10.0 mL). The mixture wassuccessively extracted with DCM (3×8.0 mL) and the combined organiclayer were dried (Na₂SO₄), filtered and concentrated under reducedpressure. The crude was purified by silica gel chromatography (24 gcartridge) with EtOAc and hexanes (5-25%) to produce[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-[(2R,6S)-3-azido-6-[[benzyl(benzyloxycarbonyl)amino]methyl]tetrahydropyran-2-yl]oxy-cyclohexyl]acetate(2 diastereomers, 144 mg, 74%) as an oil. LCMS m/z: [M+H]⁺: 677.20;(A05) retention time=2.86 m.

Step 8

BenzylN-[[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]methyl]-N-benzyl-carbamate

NaOMe (25 wt %, 306 μL, 1.06 mmol) was added dropwise to a solution of[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-[(2R,6S)-3-azido-6-[[benzyl(benzyloxycarbonyl)amino]methyl]tetrahydropyran-2-yl]oxy-cyclohexyl]acetate(92 mg, 136 μmol) in MeOH (2.0 mL) at ambient temperature. After 60 min,HOAc (122 μL, 2.13 mmol) was added to the reaction mixture dropwise andall volatiles were removed under reduced pressure. The crude waspurified by silica gel chromatography (24 g cartridge) with EtOAc andhexanes (10-40%) to produce the title compound as an oil (28 mg, 22%)and benzylN-[[(2S,5S,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]methyl]-N-benzyl-carbamateas a solid (38 mg, 30%). They has the same retention time and MS. LCMSm/z: ES⁺[M+H]⁺: 379.27; (A05) retention time=2.63 m.

Step 9

(1S,2R,3R,4S,6R)-4,6-Diamino-3-[(2R,3R,6S)-3-amino-6-(aminomethyl)tetrahydropyran-2-yl]oxy-cyclohexane-1,2-diol

Pd(OH)₂/C (10 wt %, 8 mg, 5.7 μmol) was added to a solution of benzylN-[[(2S,5R,6S)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]methyl]-N-benzyl-carbamate(8 mg, 13.5 μmol) in MeOH (2.5 mL) under N₂ at ambient temperature. H₂was bubbled through the suspension for 15 min. After 17 h, the solutionwas filtered through a frit (0.22 μm diameter) and the filtrate wasconcentrated under reduced pressure, then lyophilized to provide thetitle compound as a wax (3.8 mg, 92%). ¹H NMR (500 MHz, MeOD) δ 5.22 (d,J=3.6 Hz, 1H), 3.92-3.84 (m, 1H), 3.39 (t, J=9.1 Hz, 1H), 3.24 (t, J=9.3Hz, 1H), 3.07 (t, J=9.4 Hz, 1H), 2.86-2.79 (m, 2H), 2.77 (dd, J=13.1,3.6 Hz, 1H), 2.70-2.63 (m, 2H), 2.01 (dt, J=8.4, 3.9 Hz, 1H), 1.78-1.67(m, 3H), 1.44-1.38 (m, 1H), 1.24 (dd, J=24.9, 12.2 Hz, 1H).

Example 12

Step 1 (2S)-3,4-dihydro-2H-pyran-2-carbaldehyde oxime

TEMPO (137 mg, 876 μmol) was added to a suspension of(2S)-3,4-dihydro-2H-pyran-2-yl)methanol (1.0 g, 8.76 mmol) and(diacetoxyiodo)benzene (DIB) (4.23 g, 13.1 mmol) in DCM (10.0 mL) atambient temperature. After 4.5 h, the solution was poured into a 1:1mixture of NaHCO₃/Na₂S₂O₃ (30.0 mL) and extracted with DCM (3×15.0 mL).To the combined organic layers was added MeCN (5.0 mL) and hydroxylamine(50% aq., 1.0 mL, 16.3 mmol). After 2 h, all volatiles were removedunder reduced pressure. The material was purified by silica gelchromatography (24 g cartridge) with EtOAc and hexanes (0-20%) toprovide the title compound (2 oxime isomers, 436 mg, 39%) as an oil. ForIEMPO/DIB oxidation: see Tetrahedron Letters, 2009, 50, 2693.

Step 2 (2S)-3,4-dihydro-2H-pyran-2-carbonitrile

MsCl (398 μL, 5.14 mmol) was added dropwise (Caution: violent reaction)to a solution of (2S)-3,4-dihydro-2H-pyran-2-carbaldehyde oxime (436 mg,3.43 mmol) and Et3N (1.67 mL, 12.0 mmol) in dry DCM (6.0 mL) under N₂ at0° C. and ice bath was removed. After 30 min, the material was filteredthrough silica gel (5.0 g) and eluted with DCM (30 mL). The filtrate wascarefully concentrated and purified by silica gel chromatography (24 gcartridge, wet loading) with DCM and the fractions were carefullyconcentrated to provide a solution of the title compound. ¹H NMR (400MHz, CDCl₃) δ 6.30 (dt, J=6.3, 1.7 Hz, 1H), 4.91-4.82 (m, 2H), 2.34-2.19(m, 1H), 2.17-2.03 (m, 3H). Note: The product contains 43 wt % EtOAcfrom ISCO system and 28 wt % DCM by ¹H NMR. The material was not fullyconcentrated because of the volatility of(2S)-3,4-dihydro-2H-pyran-2-carbonitrile.

Step 3 Benzyl N-[1-[(2S)-3,4-dihydro-2H-pyran-2-yl]cyclopropyl]carbamate

Ti(OiPr)₄ (1.09 mL, 3.67 mmol) was added to a suspension of EtMgBr (3.0M in ether, 2.44 mL, 7.33 mmol) in dry THF (5.0 mL) under N₂ at −78° C.After 30 min, a solution of (2S)-3,4-dihydro-2H-pyran-2-carbonitrile(320 mg, 2.93 mmol, carefully co-evaporated with 3×25.0 mL hexane) indry THF (3.0 mL) was added dropwise and the mixture was warmed to roomtemperature. After 40 min, BF₃.OEt₂ (724 μL, 5.86 mmol) was added to thereaction mixture dropwise. After another 30 min, the solution was cooledto 0° C. and 1.0 M solution of NaOH (14.7 mL, 14.7 mmol) was addedquickly dropwise. After another 10 min, CbzCl (625 μL, 4.40 mol) wasadded at ambient temperature and the reaction mixture was stirred for 1h. The mixture was diluted with water (30.0 mL) and DCM (30.0 mL) Thelayers were separated, and the aqueous layer was extracted with DCM(2×10.0 mL). The combined organic layers were dried (Na₂SO₄), filteredand concentrated under reduced pressure. The material was purified bysilica gel chromatography (25 g cartridge) using a gradient of 0-20%EtOAc in hexane as eluent to provide the title compound (225 mg, 28%) asa solid.¹H NMR (500 MHz, CDCl₃) δ 7.39-7.28 (m, 5H), 6.35 (d, J=5.4 Hz,1H), 5.25 (s, 1H), 5.06 (s, 2H), 4.69-4.60 (m, 1H), 3.43 (d, J=10.1 Hz,1H), 2.13-1.88 (m, 3H), 1.65 (ddd, J=25.1, 12.4, 6.2 Hz, 1H), 1.13-1.02(m, 1H), 0.96-0.78 (m, 3H). MS ESI [M+H]⁺274.0.

Step 4 BenzylN-[1-[(2S)-6-hydroxy-5-iodo-tetrahydropyran-2-yl]cyclopropyl]carbamate

I₂ (71 mg, 281 μmol) was added to a suspension ofN-benzyl-N-[1-[(2S)-3,4-dihydro-2H-pyran-2-yl]cyclopropyl]carbamate (100mg, 275 μmol) and NaHCO₃ (46 mg, 550 mmol) in a mixture H₂O/MeCN (1:1)(3.0 mL) at ambient temperature. After 20 min, the volatiles wereevaporated, and the residue was partitioned in between DCM (10.0 mL) andbrine (10.0 mL). The aqueous layer was extracted with DCM (2×5.0 mL) andthe combined organic layers were dried (Na₂SO₄), filtered andconcentrated under reduced pressure to provide the title compound (>2diastereomers, 140 mg, 92%) as a solid, which was used in the next stepwithout further purification. MS ESI [M+H]⁺417.9.

Step 5 BenzylN-[1-[(2S)-5-azido-6-oxo-tetrahydropyran-2-yl]cyclopropyl]carbamate

4 Å sieves (150 mg) and PDC (252 mg, 671 μmol) was added to a solutionof benzylN-[1-[(2S)-6-hydroxy-5-iodo-tetrahydropyran-2-yl]cyclopropyl]carbamate(140 mg, 336 μmol) in dry DCM (3.5 mL) under N₂ at ambient temperature.After 20 h, the material was filtered through a silica gel plug (1.2 mL)and was eluted with EtOAc (10.0 mL). The filtrate was concentrated underreduced pressure. The crude iodolactone (135 mg) was dissolved in dryDMF (0.40 mL) under N2 and then NaN₃ (33 mg, 503 μmol) was added. After1 h, the solution was filtered through a silica gel plug (1.0 mL) andeluted with EtOAc (12.0 mL). The filtrate was concentrated under reducedpressure. The mixture was re-dissolved in EtOAc and filtered through asilica gel plug (1.0 mL) and eluted with EtOAc (12.0 mL). The filtratewas concentrated under reduced pressure then lyophilized to produce thetitle compound (100 mg, 90%) as an oil, which was used in the nextreactions without further purification. MS ESI [M+H]⁺330.9.

Step 6 BenzylN-[1-[(2S,5R)-5-azido-6-hydroxy-tetrahydropyran-2-yl]cyclopropyl]carbamate

DIBAL-H (1 M, 484 μL, 484 μmol) in toluene was dropwise added to asolution of benzylN-[1-[(2S)-5-azido-6-oxo-tetrahydropyran-2-yl]cyclopropyl]carbamate (100mg, 303 μmol) in dry DCM (4.0 mL) at −78° C. under N₂ and the reactionmixture was stirred for 50 min. Acetone (150 μL) and saturated potassiumsodium tartrate (5.0 mL) were added to the solution slowly. The mixturewas warmed to room temperature and vigorously stirred for 16 h. Themixture was extracted with DCM (2×10 mL). The combined organic layerswere dried (Na₂SO₄), filtered and concentrated under reduced pressure.The material was purified by silica gel chromatography (12 g cartridge)using a gradient of 15-40% with EtOAc and hexane as eluent and waspurified by silica gel chromatography (12 g cartridge) using a gradientof 5-30% EtOAc and hexane as eluent to provide the title compound (44mg, 44%) as a solid. MS ESI [M+Na]⁺355.1.

Step 7[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-[(2R,3R,6S)-3-azido-6-[1-(benzyloxycarbonylamino)cyclopropyl]tetrahydropyran-2-yl]oxy-cyclohexyl]acetate

CCl₃CN (60 μL, 860 μmol) was added dropwise to a suspension of benzylN-[1-[(2S,5R)-5-azido-6-hydroxy-tetrahydropyran-2-yl]cyclopropyl]carbamate(44 mg, 119 μmol) and K₂CO₃ (49 mg, 357 μmol) in dry DCM (1.0 mL) atambient temperature under N₂ and the solution was stirred for 64 h. Themixture was filtered through cotton and the filtrate was concentratedunder N₂ stream, followed by high-vacuum. To the residue was added[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-hydroxy-cyclohexyl]acetate (50mg, 167 μmol) and ground 4 Å sieves (300 mg) and the mixture wasdissolved in dry DCM (1.0 mL). The suspension was stirred at ambienttemperature for 40 min. The mixture was cooled to 0° C. and BF₃.OEt₂ (60μL, 477 μmol) was added dropwise with vigorous stirring. The reactionmixture was warmed to ambient temperature and stirred for another 30min. To the mixture was added Et₃N (100 μL) and the solution wasfiltered through silica gel (0.30 g) and eluted EtOAc (6.0 mL). Thefiltrate was concentrated and purified by preparative HPLC (BEH 30×150mm C18 ACN/AmForm 60-70%) to provide the title compound (21 mg, 29%) asa solid. ¹H NMR (500 MHz, CDCl₃) δ 7.42-7.29 (m, 5H), 5.18 (s, 1H), 5.14(d, J=9.8 Hz, 1H), 5.11 (s, 1H), 5.05 (s, 2H), 4.91 (t, J=10.0 Hz, 1H),3.68 (dd, J=16.4, 6.7 Hz, 2H), 3.61 (ddd, J=12.6, 10.2, 4.6 Hz, 1H),3.54-3.41 (m, 1H), 3.00 (dt, J=6.6, 3.9 Hz, 1H), 2.34 (dt, J=13.3, 4.6Hz, 1H), 2.07 (s, 3H), 2.07 (s, 3H), 2.03-1.92 (m, 2H), 1.92-1.85 (m,1H), 1.57-1.45 (m, 2H), 1.10-1.02 (m, 1H), 0.91 (ddd, J=11.1, 6.6, 4.4Hz, 1H), 0.88-0.81 (m, 1H), 0.81-0.74 (m, 1H). MS ESI [M+H]⁺613.3.

Step 8[(1S,2S,3R,4S,6R)-4,6-diazido-3-[(2R,3R,6S)-3-azido-6-[1-(benzyloxycarbonylamino)cyclopropyl]tetrahydropyran-2-yl]oxy-2-hydroxy-cyclohexyl]acetate

NaOMe (25 wt %, 40 μL, 173 μmol) was added dropwise to a suspension of[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-[(2R,3R,6S)-3-azido-6-[1-(benzyloxycarbonylamino)cyclopropyl]tetrahydropyran-2-yl]oxy-cyclohexyl]acetate(21 mg, 34 μmol) in MeOH (1.0 mL) at ambient temperature and stirred for30 min. The mixture was warmed to 40° C. and stirred for 30 min. Thesolution was cooled to room temperature and AcOH (20 μL, 343 μmol) wasadded to the reaction mixture dropwise and all volatiles were evaporatedunder reduced pressure. The material was filtered through silica gel(0.30 g) and eluted with EtOAc (6.0 mL). The filtrate was concentratedunder reduced pressure and the residue was dissolved in dry DCM (0.50mL) under N₂ and then pyridine (17 μL, 206 μmol) and Ac₂O (6.5 μL, 69μmol) were added and the reaction mixture was stirred for 20 h. MeOH(100 μL) was added and all volatiles were evaporated under reducedpressure. The material was lyophilized to afford the title compound (20mg, 99%) as a solid, which was used in the next step without furtherpurification. ¹H NMR (500 MHz, CDCl₃) δ 7.39-7.28 (m, 5H), 5.34-5.23 (m,2H), 5.16-5.01 (m, 2H), 4.90 (dd, J=13.6, 6.3 Hz, 1H), 3.70-3.57 (m,2H), 3.52-3.41 (m, 2H), 3.40-3.27 (m, 2H), 2.35-2.25 (m, 1H), 2.16 (s,3H), 1.99-1.88 (m, 3H), 1.57-1.47 (m, 2H), 1.11-1.01 (m, 1H), 0.93-0.81(m, 2H), 0.81-0.74 (m, 1H). MS ESI [M+H]⁺571.2.

Step 9[(2R,3R,4R,5S)-4-acetoxy-5-[(1S,2S,3R,5S,6R)-2-acetoxy-3,5-diazido-6-[(2R,3R,6S)-3-azido-6-[1-(benzyloxycarbonylamino)cyclopropyl]tetrahydropyran-2-yl]oxy-cyclohexoxy]-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-tetrahydrofuran-2-yl]methylacetate

CCl₃CN (44 μL, 438 μmol) was added dropwise to a suspension of[(2R,3R,4R)-4-acetoxy-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)ptetrahydropyran-2-yl]oxy-5-hydroxy-tetrahydrofuran-2-yl]methylacetate (46 mg, 87 μmol) and K₂CO₃ (36 mg, 263 μmol) in dry DCM (1.0 mL)at ambient temperature under N₂ and stirred for 64 h. The solution wasfiltered through cotton and the filtrate was concentrated under N₂stream, and then dried under reduced pressure. To the crude was added[(1S,2S,3R,4S,6R)-4,6-diazido-3-[(2R,3R,6S)-3-azido-6-[1-(benzyloxycarbonylamino)cyclopropyl]tetrahydropyran-2-yl]oxy-2-hydroxy-cyclohexyl]acetate(20 mg, 35 μmol) in DCM (3.0 mL) and all volatiles were evaporated underN₂ stream. To the mixture was added ground 4 Å sieves (300 mg) and themixture was dissolved in dry DCM (1.0 mL). The suspension was stirred atambient temperature for 30 min, then cooled to 0° C., followed by theaddition of BF₃.OEt₂ (43 μL, 351 μmol) and the mixture was stirred atambient temperature for another 1 h. Et₃N (100 μL) was added and themixture was filtered through a silica gel pad (0.30 g) and eluted withEtOAc (5.0 mL). All volatiles were evaporated under reduced pressure andthe material was purified by reversed phase chromatography (C18, 12 gcartridge) with ACN and 0.1% aqueous formic acid (50-100%) to afford thetitle compound (25 mg, 66%) as a solid. ¹H NMR (500 MHz, CDCl₃) δ7.40-7.30 (m, 5H), 5.76 (d, J=2.8 Hz, 1H), 5.35 (d, J=2.5 Hz, 2H), 5.06(d, J=4.0 Hz, 2H), 5.02 (t, J=2.8 Hz, 1H), 4.93 (dd, J=12.1, 6.5 Hz,2H), 4.87 (d, J=1.8 Hz, 1H), 4.71-4.68 (m, 1H), 4.44-4.37 (m, 2H), 4.33(td, J=6.1, 2.1 Hz, 1H), 4.21 (dd, J=12.0, 5.7 Hz, 1H), 4.08 (ddd,J=8.1, 4.2, 1.8 Hz, 1H), 3.88 (t, J=8.6 Hz, 1H), 3.72 (t, J=8.7 Hz, 1H),3.63-3.53 (m, 2H), 3.49-3.39 (m, 2H), 3.32 (s, 1H), 3.23 (dd, J=12.6,4.3 Hz, 1H), 2.89 (dt, J=7.8, 3.1 Hz, 1H), 2.32-2.21 (m, 1H), 2.17 (s,3H), 2.15 (s, 6H), 2.12 (s, 3H), 2.06-2.00 (m, 1H), 1.98-1.82 (m, 2H),1.50-1.41 (m, 2H), 1.13-1.02 (m, 1H), 0.91-0.76 (m, 4H). MS ESI[M+H]⁺1083.4.

Step 10 BenzylN-[1-[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2-[(2S,3R,4S,5R)-4-[(2R,3R,4R,5S,6S)-3-azido-6-(azidomethyl)-4,5-dihydroxy-tetrahydropyran-2-yl]oxy-3-hydroxy-5-thydroxymethyl)tetrahydrofuran-2-yl]oxy-3-hydroxy-cyclohexoxy]tetrahydropyran-2-yl]cyclopropyl]carbamate

NaOMe (25 wt %, 63 μL, 277 μmol) was added dropwise to a solution of[(2R,3R,4R,5S)-4-acetoxy-5-[(1S,2S,3R,5S,6R)-2-acetoxy-3,5-diazido-6-[(2R,3R,6S)-3-azido-6-[1-(benzyloxycarbonylamino)cyclopropyl]tetrahydropyran-2-yl]oxy-cyclohexoxy]-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-tetrahydrofuran-2-yl]methylacetate (25 mg, 23 mmol) in MeOH (1.0 mL) at ambient temperature andstirred for 75 min. AcOH (24 μL, 416 μmol) was added dropwise and allvolatiles were evaporated under reduced pressure. The material wasfiltered through silica gel (0.30 g) and eluted with EtOAc (6.0 mL). Thefiltrate was concentrated under reduced pressure and the material waspurified by silica gel chromatography (4 g cartridge) using a gradientof 50-100% EtOAc in hexane as eluent and was further purified bysupercritical fluid chromatography (Lux Cellulose-2 10×250 mm-25ACN-EtOH-10 mL/min) to provide the title compound (8 mg, 39%) as asolid. MS ESI [M+NH₄]⁺890.3; MS ESI [M+Na]⁺895.3.

Step 11(2S,3S,4R,5R,6R)-5-amino-2-(aminomethyl)-6-[(2R,3S,4R,5S)-5-[(1R,2R,3S,5R,6S)-3,5-diamino-2-[(2R,3R,6S)-3-amino-6-(1-aminocyclopropyl)tetrahydropyran-2-yl]oxy-6-hydroxy-cyclohexoxy]-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl]oxy-tetrahydropyran-3,4-dio1,2,2,3,3,4,4,4-heptafluorobutanoicacid

Pd(OH)₂/C (10 wt %, 2.6 mg, 1.8 μmol) was added to a solution of benzylN-[1-[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2-[(2S,3R,4S,5R)-4-[(2R,3R,4R,5S,6S)-3-azido-6-(azidomethyl)-4,5-dihydroxy-tetrahydropyran-2-yl]oxy-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]oxy-3-hydroxy-cyclohexoxy]tetrahydropyran-2-yl]cyclopropyl]carbamate(8 mg, 9 μmol) in MeOH (3.0 mL) under N₂ at ambient temperature. H₂ wasbubbled into the solution for 15 min and the suspension was hydrogenatedfor 21 h. The material was filtered through a frit (0.45 μm diameter)and the filtrate was concentrated under reduced pressure. The materialwas purified by a HFBA-coupled preparative HPLC to provide the titlecompound (hexa-HFBA salt, 10.8 mg, 62%) as a solid. ¹H NMR (500 MHz,MeOD) δ 5.91 (d, J=3.4 Hz, 1H), 5.47 (d, J=3.0 Hz, 1H), 5.31 (d, J=1.4Hz, 1H), 4.49 (t, J=5.3 Hz, 1H), 4.31 (dd, J=4.8, 3.1 Hz, 1H), 4.30-4.27(m, 1H), 4.22 (td, J=5.3, 3.0 Hz, 1H), 4.17-4.10 (m, 2H), 3.99 (dd,J=12.0, 2.3 Hz, 1H), 3.91-3.83 (m, 2H), 3.74 (dd, J=12.1, 5.2 Hz, 1H),3.70-3.66 (m, 1H), 3.66-3.60 (m, 1H), 3.55 (ddd, J=12.9, 10.4, 4.0 Hz,1H), 3.49 (dt, J=12.9, 4.1 Hz, 1H), 3.46-3.42 (m, 1H), 3.37 (dd, J=13.4,7.2 Hz, 1H), 3.29-3.22 (m, 2H), 2.48 (dt, J=12.4, 4.1 Hz, 1H), 2.16-2.02(m, 2H), 1.97-1.88 (m, 1H), 1.81 (dd, J=13.3, 2.3 Hz, 1H), 1.64-1.52 (m,1H), 1.08-0.91 (m, 4H). MS (ESI) [M+H]⁺609.4.

Example 13

Step 1[(1S,2S,3R,4S,6R)-4,6-diazido-3-[(2R,3R,6S)-3-azido-6-[[benzyl(benzyloxycarbonyl)amino]methyl]tetrahydropyran-2-yl]oxy-2-hydroxy-cyclohexyl]acetate

To a solution of benzylN-[[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]methyl]-N-benzyl-carbamate(see Example 11 for synthesis, 4.4 g, 4.42 mmol) and pyridine (3.60 mL,44.5 mmol) in dry DCM (400 mL) at room temperature was added Ac₂O (3.51mL, 37.1 mmol) and the reaction mixture was stirred for 20 h. MeOH (5mL) was added, and the volatiles were removed under reduced pressure.The material was purified by MPLC on silica gel (220 g, liquid loadingwith toluene) using a gradient of 0-35% EtOAc in hexane as eluent toprovide the title compound (4.0 g, 85%) as a solid. MS (ESI)[M+H]⁺635.3.

Step 2 Benzyl((R)-1-((2S,5R,6R)-5-azido-6-(((1R,2R,3S,4R,6S)-4,6-diazido-2-(((2S,3R,4S,5R)-4-(((2R,3R,4R,5S,6S)-3-azido-6-(azidomethyl)-4,5-dihydroxytetrahydro-2H-pyran-2-yl)oxy)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)oxy)-3-hydroxycyclohexyl)oxy)tetrahydro-2H-pyran-2-yl)ethyl)(benzyl)carbamate

To a mixture of[(2R,3R,4R)-4-acetoxy-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-5-hydroxy-tetrahydrofuran-2-yl]methylacetate (3.08 g, 5.80 mmol) and K₂CO₃ (2.79 g, 20.2 mmol) in DCM (500mL) was added CCl₃CN (2.53 mL, 25.2 mmol) at room temperature. Themixture was stirred at room temperature for 18 h, then filtered onCelite, rinsed with DCM and concentrated under reduced pressure. To theabove material in dry DCM (500 mL) was added[(1S,2S,3R,4S,6R)-4,6-diazido-3-[(2R,3R,6S)-3-azido-6-[(1R)-1-[benzyl(benzyloxycarbonyl)amino]ethyl]tetrahydropyran-2-yl]oxy-2-hydroxy-cyclohexyl]acetate(3.20 g, 5.04 mmol) followed by activated 3 Å sieves (5 g). The mixturewas cooled to −78° C. and then BF₃.OEt₂ (1.56 mL, 12.6 mmol) was addeddropwise. The acetone-dry ice bath was removed, and the reaction mixturewas slowly warmed to room temperature, and then saturated NaHCO₃ (40 mL)was added. The separated aqueous layer was extracted with DCM (3×150mL). The combined organic layers were washed with brine, then dried(MgSO₄), filtered and concentrated under reduced pressure. The residuewas dissolved in MeOH (200 mL) then NaOMe (4.62 M in MeOH, 3.62 mL, 16.7mmol) was added at room temperature and the resulting mixture wasstirred for 1 h. The mixture was diluted with saturated NH₄Cl (300 mL)and the separated aqueous layer was extracted with DCM (3×300 mL). Thecombined organic layers were washed with brine, then dried (MgSO₄),filtered and concentrated under reduced pressure. The material waspurified on C18 silica (120 g) by IVIPLC using a gradient of 30-100% Bin A (A: 10 mm AmFor pH 3.8, B: acetonitrile) to provide the titlecompound (1.90 g, 41%) as a solid. MS (ESI) [M+Na]⁺959.4.

Step 3(2S,3S,4R,5R,6R)-5-amino-2-(aminomethyl)-6-(((2R,3S,4R,5S)-5-(((1R,2R,3S,5R,6S)-3,5-diamino-2-(((2R,3R,6S)-3-amino-6-(aminomethyl)tetrahydro-2H-pyran-2-yl)oxy)-6-hydroxycyclohexyl)oxy)-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)tetrahydro-2H-pyran-3,4-dioltris(sulfate)

In a 2 neck flask equipped with a reflux condenser were benzyl(((2S,5R,6R)-5-azido-6-(((1R,2R,3S,4R,6S)-4,6-diazido-2-(((2S,3R,4S,5R)-4-(((2R,3R,4R,5S,6S)-3-azido-6-(azidomethyl)-4,5-dihydroxytetrahydro-2H-pyran-2-yl)oxy)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)oxy)-3-hydroxycyclohexyl)oxy)tetrahydro-2H-pyran-2-yl)methyl)(benzyl)carbamate (1.60 g , 0.04 mmol) and Pd/C (10% dry on carbon, 727 mg,0.683 mmol) following by anhydrous MeOH (500 mL). Nitrogen was bubbledfor 5 min, then ammonium formate (1.62 g, 25.6 mmol) was added. Themixture was heated at 63° C. for 5 h under N₂, then cooled to roomtemperature with an ice-bath. The mixture was filtered over Celite,rinsed with MeOH and concentrated under reduced pressure. The materialwas purified by preparative HPLC using a gradient 27-37% B in A over 6.9min (A: 0.3% HCOOH, 0.3% HFBA, B: 0.3% HFBA in ACN) on C18 Gemini-NX30×150 mm provide the title compound (850 mg, 27%) as a 6×HFBA salt. Thesalt was dissolved in water (10 mL), then the pH was adjusted to 7 using0.1 N aqueous NH₄OH. Ammonium sulfate (3 eq, 180 mg, 1.37 mmol) was thenadded. The mixture was stirred at room temperature for 5 min, thenfiltered with 0.40 μM syringe filter and added dropwise to MeOH (450 mL)under vigorous stirring. The suspension was filter on Fine frit andrinsed with MeOH (20 mL). The mother liquor was discarded and the solidwas dissolved in water (50 mL) and lyophilized to provide the titlecompound (282 mg, 19%) as a solid. ¹H-INMR (500 MHz, D₂O) δ 5.94 (d,J=3.6 Hz, 1H), 5.44 (d, J=2.3 Hz, 1H), 5.33 (d, J=1.7 Hz, 1H), 4.56 (dd,J=6.7, 4.8 Hz, 1H), 4.47 (dd, J=4.8, 2.3 Hz, 1H), 4.36 (ddd, J=7.0, 3.8,1.4 Hz, 1H), 4.29-4.24 (m, 2H), 4.16 (dd, J=12.6, 6.6 Hz, 2H), 3.98-3.90(m, 2H), 3.86-3.84 (m, 1H), 3.81-3.74 (m, 2H), 3.64-3.61 (m, 1H),3.61-3.55 (m, 1H), 3.54-3.44 (m, 2H), 3.42-3.35 (m, 2H), 3.26 (dd,J=13.4, 3.3 Hz, 1H), 3.10 (dd, J=13.5, 8.2 Hz, 1H), 2.74-2.43 (m, 1H),2.12-1.91 (m, 4H), 1.66-1.54 (m, 1H). MS (ESI) [M+H]⁺583.5.

Example 14

Step 1(1S,2R,3R,4S,6R)-4,6-diazido-3-[(2R,3S,5R,6R)-3-azido-6-(azidomethyl)-4,4-difluoro-5-hydroxy-tetrahydropyran-2-yl]oxy-cyclohexane-1,2-diol

[(2R,3R,5S,6S)-5-azido-2-(azidomethyl)-4,4-difluoro-6-hydroxy-tetrahydropyran-3-yl]acetate(preparation below, 250 mg, 0.57 mmol),[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-hydroxy-cyclohexyl]acetate(384 mg, 1.29 mmol) and grounded 4 Å molecular sieves were added to adry round bottom flask. The mixture was dissolved in dry DCM (8.0 mL)and the suspension was stirred at ambient temperature for 45 min underN₂. The solution was cooled to −78° C. and then BF₃.Et₂O (0.53 mL, 4.29mmol) was added dropwise with vigorous stirring and the reaction wasstirred at −78° C. for 1 h. The solution was warmed to ambienttemperature and stirred for another 3 h. The reaction was quenched withsaturated NaHCO₃ (50.0 mL) and the aqueous layer was extracted with DCM(3×50 mL). The combined organic layers were dried (Na₂SO₄), filtered andconcentrated under reduced pressure.

Step 2

NaOMe (25 wt %, 0.56 mL, 2.58 mmol) was added dropwise to a solution ofthe crude in MeOH (2.0 mL) at ambient temperature. After 70 min, AcOH(0.26 mL, 4.58 mmol) was added and the volatiles were removed underreduced pressure. The material was purified by silica gel chromatography(24 g, dry loading) using a gradient of 0-40% EtOAc in hexane as eluentto provide the title compound (60.2 mg, 24%). ¹H NMR (400 MHz, CD₃OD) δ5.81 (t, J=4.2 Hz, 1H), 4.50 (ddd, J=10.1, 4.5, 2.8 Hz, 1H), 3.84-3.70(m, 1H), 3.62-3.40 (m, 7H), 3.29 (t, J=9.5 Hz, 1H), 2.31 (dt, J=12.9,4.4 Hz, 1H), 1.47 (dd, J=24.8, 12.2 Hz, 1H).

Step 3[(1S,2S,3R,4S,6R)-3-[(2R,3S,5R,6R)-5-acetoxy-3-azido-6-(azidomethyl)-4,4-difluoro-tetrahydropyran-2-yl]oxy-4,6-diazido-2-hydroxy-cyclohexyl]acetate

To a solution of(1S,2R,3R,4S,6R)-4,6-diazido-3-[(2R,3S,5R,6R)-3-azido-6-(azidomethyl)-4,4-difluoro-5-hydroxy-tetrahydropyran-2-yl]oxy-cyclohexane-1,2-diol(60 mg, 134 μmol) in dry DCM (2 mL) at ambient temperature, was addedpyridine (87 μL, 1.08 mmol) followed by Ac₂O (76 μL, 807 μmol) and thereaction mixture was stirred for 20 h. The volatiles were evaporatedunder reduced pressure and the material was purified silica gelchromatography (4 g, dry loading) using a gradient of 10-30% EtOAc inhexane as eluent to provide the title compound (56.9 mg, 80%). ¹H NMR(400 MHz, CDCl₃) δ 5.53 (t, J=4.3 Hz, 1H), 5.17 (ddd, J=19.5, 10.4, 4.0Hz, 1H), 4.86 (t, J=9.9 Hz, 1H), 4.52 4.43 (m, 1H), 3.71 (td, J=9.3, 4.2Hz, 1H), 3.62 (dt, J=23.3, 4.2 Hz, 1H), 3.55-3.22 (m, 6H), 2.36 (dt,J=13.1, 4.3 Hz, 1H), 2.21-2.11 (m, 6H), 1.62-1.53 (m, 1H).

Step 4[(2R,3R,4R,5S)-4-acetoxy-5-[(1S,2S,3R,5S,6R)-2-acetoxy-6-[(2R,5R,6R)-5-acetoxy-3-azido-6-(azidomethyl)-4,4-difluoro-tetrahydropyran-2-yl]oxy-3,5-diazido-cyclohexoxy]-3-[(2R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-tetrahydrofuran-2-yl]methylacetate

CCl₃CN (0.16 mL, 1.64 mmol) was added dropwise to a mixture of[(2R,3R,4R)-4-acetoxy-3-[(2R,3R, 4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-5-hydroxy-tetrahydrofuran-2-yl]methylacetate (174 mg, 0.33 mmol) and K₂CO₃ (136 mg, 0.98 mmol) in dry DCM (10mL) at room temperature under N₂. The mixture was stirred at roomtemperature for 18 h, then filtered with a filter syringe and rinsedwith DCM. The filtrate was concentrated under reduced pressure and thecrude imidate was used directly in the next step.

To a solution of[(1S,2S,3R,4S,6R)-3-[(2R,3S,5R,6R)-5-acetoxy-3-azido-6-(azidomethyl)-4,4-difluoro-tetrahydropyran-2-yl]oxy-4,6-diazido-2-hydroxy-cyclohexyl]acetate(58 mg, 0.11 mmol) in DCM (10 mL) was added the crude imidate followedby 4 Å molecular sieves and the mixture was stirred for 2 h and thencooled to −78° C. BF₃.OEt₂ (0.068 mL, 0.55 mmol) was added dropwise. Themixture was stirred at −78° C. for 2 h and then at room temperature for2 h. The mixture was diluted with saturated NaHCO₃ (10 mL) and theseparated aqueous layer was extracted with DCM (2×10 mL). The combinedorganic layers were washed with brine, dried (Na₂SO₄), filtered andconcentrated under reduced pressure to afford the title compound. MS ESI[M+NH₄]⁺1060.4.

Step 5(2S,3S,4R,5R,6R)-5-azido-2-(azidomethyl)-6-[(2R,3S,4R,5S)-5-[(1R,2R,3S,5R,6S)-3,5-diazido-2-[(2R,3S,5R,6R)-3-azido-6-(azidomethyl)-4,4-difluoro-5-hydroxy-tetrahydropyran-2-yl]oxy-6-hydroxy-cyclohexoxy]-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl]oxy-tetrahydropyran-3,4-diol

To a solution of crude[(2R,3R,4R,5S)-4-acetoxy-5-[(1S,2S,3R,5S,6R)-2-acetoxy-6-[(2R,5R,6R)-5-acetoxy-3-azido-6-(azidomethyl)-4,4-difluoro-tetrahydropyran-2-yl]oxy-3,5-diazido-cyclohexoxy]-3-[(2R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-tetrahydrofuran-2-yl]methylacetate (114 mg, 109 μmol) in MeOH (2 mL) at ambient temperature, wasadded NaOMe (25 wt %, 337 μL, 1.31 mmol) dropwise and the reactionmixture was stirred for 50 min. The mixture was diluted with AcOH (125mL, 2.18 mmol) and the volatiles were evaporated under reduced pressure.The material was purified by silica gel chromatography (12 g cartridge)using a gradient of 5-35% EtOAc and hexane as eluent and was furtherpurified by reverse phase (C18, 120 g Biotage) using 50% B in A to 100%B (B=ACN 0.1% HCOOH, A=H₂O 0.1% HCOOH) to provide the title compound.The material purified with preparative HPLC (ACN, AmFor, CSH column) togive the title compound (16 mg, 19%, 2 steps from[(1S,2S,3R,4S,6R)-3-[(2R,3S,5R,6R)-5-acetoxy-3-azido-6-(azidomethyl)-4,4-difluoro-tetrahydropyran-2-yl]oxy-4,6-diazido-2-hydroxy-cyclohexyl]acetate).¹H NMR (400 MHz, CD₃OD) δ 5.92 (t, J=4.1 Hz, 1H), 5.32 (d, J=2.0 Hz,1H), 5.10 (d, J=1.8 Hz, 1H), 4.46 (ddd, J=10.2, 4.7, 2.6 Hz, 1H), 4.37(dd, J=6.6, 4.6 Hz, 1H), 4.29 (dd, J=4.5, 2.0 Hz, 1H), 4.11 (td, J=6.1,2.7 Hz, 1H), 3.99 (ddd, J=8.5, 4.4, 1.9 Hz, 1H), 3.90 (t, J=3.4 Hz, 1H),3.82 (dd, J=11.9, 2.7 Hz, 1H), 3.74-3.29 (m, 14H), 2.23 (dt, J=12.8, 4.0Hz, 1H), 1.46-1.32 (m, 1H). MS ESI [M+NH₄]⁺808.2.

Step 6(2S,3S,4R,5R,6R)-5-amino-2-(aminomethyl)-6-[(2R,3S,4R,5S)-5-[(1R,2R,3S,5R,6S)-3,5-diamino-2-[(2R,3S,5R,6R)-3-amino-6-(aminomethyl)-4,4-difluoro-5-hydroxy-tetrahydropyran-2-yl]oxy-6-hydroxy-cyclohexoxy]-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl]oxy-tetrahydropyran-3,4-diol

To(2S,3S,4R,5R,6R)-5-azido-2-(azidomethyl)-6-[(2R,3S,4R,5S)-5-[(1R,2R,3S,5R,6S)-3,5-diazido-2-[(2R,3S,5R,6R)-3-azido-6-(azidomethyl)-4,4-difluoro-5-hydroxy-tetrahydropyran-2-yl]oxy-6-hydroxy-cyclohexoxy]-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl]oxy-tetrahydropyran-3,4-diol(8.0 mg, 10.1 μmol) under N₂ at ambient temperature was added Pd(OH)₂/C(10 wt %, 5.0 mg, 3.5 μmol) followed by MeOH (3.0 mL) and the resultingsuspension was bubbled with H₂ for 10 min. The mixture was hydrogenatedunder hydrogen atmosphere (1 atm, balloon) for 16 h. The suspension wasfiltered through a nylon filter (0.45 μm), rinsed with MeOH and thefiltrate was concentrated under reduced pressure to give the titlecompound. The procedure was repeated to give the title compound (9.5 mgwith 74% yield in total). ¹H NMR (500 MHz, CD₃OD) δ 5.72 (s, 1H), 5.38(d, J=2.1 Hz, 1H), 4.97 (d, J=1.6 Hz, 1H), 4.45 (dd, J=6.6, 5.0 Hz, 1H),4.19 (dd, J=4.9, 2.2 Hz, 1H), 4.09 (dd, J=6.7, 3.3 Hz, 1H), 4.00-3.93(m, 2H), 3.89 (dd, J=12.2, 5.4 Hz, 1H), 3.83 (dd, J=12.3, 2.8 Hz, 1H),3.74 (dd, J=12.2, 3.6 Hz, 1H), 3.63 (t, J=9.2 Hz, 2H), 3.54-23.49 (m,2H), 3.26 (t, J=9.5 Hz, 1H), 3.22 3.10 (m, 3H), 3.02 (s, 1H), 2.96 (dd,J=13.3, 3.8 Hz, 1H), 2.86 (dt, J=17.5, 8.7 Hz, 2H), 2.73 2.66 (m, 1H),2.00 (dt, J=12.9, 4.1 Hz, 1H), 1.28-1.22 (m, 1H). MS ESI [M+H]⁺635.4.

Preparation of[(2R,3R,5S,6S)-5-azido-2-(azidomethyl)-4,4-difluoro-6-hydroxy-tetrahydropyran-3-yl]acetate

Step 1(2R,3S,4R,5R)-2-(acetoxymethyl)-6-(benzyloxy)-5-(1,3-dioxoisoindolin-2-yl)tetrahydro-2H-pyran-3,4-diyldiacetate

To a solution of 23 g(3R,4R,5S,6R)-6-(acetoxymethyl)-3-(1,3-dioxoisoindolin-2-yl)tetrahydro-2H-pyran-2,4,5-triyltriacetateand 10.4 g of benzyl alcohol in 100 mL of anhydrous DCM was added 29.7mL of BF₃ OEt₂ at 0° C. The temperature was raised to 35° C. and stirredfor 12 hours until completion. The reaction was diluted with 250 mL ofDCM and washed with 2×250 mL, ice cold water and 1×250 mL aqueous sodiumbicarbonate. The organic layer was dried, filtered, concentrated andpurified by flash chromatography to yield 22.3 g of(3R,4R,5S,6R)-6-(acetoxymethyl)-3-(1,3-dioxoisoindolin-2-yl)tetrahydro-2H-pyran-2,4,5-triyltriacetate (88% yield).

Step 22-((4aR,7R,8R,8a5)-6-(benzyloxy)-8-hydroxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)isoindoline-1,3-dione

A solution of 55 g of(2R,3S,4R,5R)-2-(acetoxymethyl)-6-(benzyloxy)-5-(1,3-dioxoisoindolin-2-yl)tetrahydro-2H-pyran-3,4-diyldiacetate in 500 mL of methanol/DCM (3:2) was cooled to −10° C. 160 mLof 0.3 M sodium methoxide (in methanol) was added and the reactioncontinued stirring at 0° C. for two hours. The reaction was neutralizedwith amberlyst resin, filtered and concentrated. The concentratedresidue was dissolved in 500 mL acetonitrile and 23.75 g of benzaldehydedimethyl acetal was added, followed by 3.6 g of CSA. The reactionstirred at room temperature for one hour until completion. The reactionwas quenched with triethylamine, concentrated and purified by flashchromatography (20% EtOAc in hexanes) to afford2-((4aR,7R,8R,8aS)-6-(benzyloxy)-8-hydroxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)isoindoline-1,3-dione(78% yield).

Step 3(4aR,7R,8R,8aS)-7-azido-6-(benzyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-ol

2-((4aR,7R,8R,8aS)-6-(benzyloxy)-8-hydroxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)isoindoline-1,3-dionewas dissolved in n-BuOH and ethylene diamine. The solution was heated to90° C. for 12 hours. The reaction was concentrated in vacuo, taken up inEtOAc, and washed with an equal volume of water. The organic layer wasconcentrated and used in the next step without further purification. 5grams of the crude intermediate was added to a solution of 300 mL ofwater/methanol (1:2) containing 100 mg CuSO₄ and 3.85 g K₂CO₃. To themixture was added 5 equivalents of TfN₃ in DCM at room temperature for12 hours. 10 g of glycine was then added and the reaction stirred anadditional 12 hours. The solid was filtered and washed with methanol.The filtrate was concentrated to 40% original volume and additionalprecipitate formed and was filtered and dissolved in DCM and dried oversodium sulfate. The dried organic portion was filtered and concentratedto yield pure(4aR,7R,8R,8aS)-7-azido-6-(benzyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-ol(92% yield).

Step 4(4aR,7S,8aR)-7-azido-6-(benzyloxy)-8,8-difluoro-2-phenylhexahydropyrano[3,2-d][1,3]dioxine

To a solution of 500 mg of(4aR,7R,8R,8aS)-7-azido-6-(benzyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-ol in 5 mL of DCM was added 520 μL of DAST and 15μL of HF/Py at 0° C. and the reaction was refluxed until completion. Thereaction was quenched with aqueous NaHCO₃ at 0° C. and the diluted withDCM. The organic layer was washed with aqueous NaHCO₃, dried, filteredand concentrated. The crude thus obtained was purified by columnchromatography to yield 183 mg of(4aR,7S,8aR)-7-azido-6-(benzyloxy)-8,8-difluoro-2-phenylhexahydropyrano[3,2-d][1,3]dioxine(36% yield).

Step 5(2R,3R,5S)-5-azido-2-(azidomethyl)-6-(benzyloxy)-4,4-difluorotetrahydro-2H-pyran-3-ol

3.4 g of(4aR,7S,8aR)-7-azido-6-(benzyloxy)-8,8-difluoro-2-phenylhexahydropyrano[3,2-d][1,3]dioxinewas dissolved in 20 mL of methanol and 219 mg of p-toluene sulfonic acidwas added. The reaction was heated at 40° C. for 1 hour untilcompletion. The reaction was quenched with 0.1 equivalents of Et₃N andconcentrated to dryness. The crude was purified by flash chromatography.2.5 g of the diol was dissolved in 24 mL of DCM/pyridine (5:3) and 1.80g of tosyl chloride was added at 0° C. The reaction was allowed to warmto room temperature and stirred for 3 hours, then diluted with DCM andwashed with 1 N HCl and saturated aqueous NaHCO₃. The organic portionwas dried, filtered and concentrated to dryness. The crude concentratewas dissolved in 30 mL of anhydrous DMF and 2.3 g of NaN₃ and thereaction heated at 70° C. for several hours.

The reaction was then diluted into EtOAc and washed with water. Theorganic portion was dried, filtered, concentrated and purified by flashchromatography to yield 2.2 g of(2R,3R,5S)-5-azido-2-(azidomethyl)-6-(benzyloxy)-4,4-difluorotetrahydro-2H-pyran-3-ol(77% yield).

Step 6(2R,3R,5S)-5-azido-2-(azidomethyl)-6-(benzyloxy)-4,4-difluorotetrahydro-2H-pyran-3-ylacetate

(2R,3R,5S)-5-azido-2-(azidomethyl)-6-(benzyloxy)-4,4-difluorotetrahydro-2H-pyran-3-olwas dissolved in pyridine and cooled to 0° C. in an ice water bath.Acetic anhydride was added and the reaction was allowed to warm to roomtemperature and stir overnight. The reaction was then concentrated invacuo, dissolved in EtOAc, and washed with 1 N HCl aq and NaHCO₃, thendried, filtered and concentrated. 100 mg of the crude was dissolved in3.8 mL of EtOAc and 3 mL of aqueous sodium bromate (179 mg/3 mL) addedin one portion. Next aqueous sodium dithionate (212 mg/6 mL) was addeddropwise and the reaction stirred vigorously until completion. Thereaction was diluted with EtOAc and washed with 1:1 aqueous NaHCO₃ andsodium thiosulfate. The organic layer was dried, filtered andconcentrated, then purified by flash chromatography (20% EtOAc inHexanes) to yield 70 mg of(2R,3R,5S)-5-azido-2-(azidomethyl)-6-(benzyloxy)-4,4-difluorotetrahydro-2H-pyran-3-ylacetate (93% yield).

Step 7(2R,3R,5S)-5-azido-2-(azidomethyl)-4,4-difluoro-6-hydroxytetrahydro-2H-pyran-3-ylacetate

1.4 grams of(2R,3R,5S)-5-azido-2-(azidomethyl)-6-(benzyloxy)-4,4-difluorotetrahydro-2H-pyran-3-ylacetate was dissolved in 54 mL EtOAc. 42 mL of aqueous sodium bromate(60 mg/mL) was added at once to the EtOAc solution, followed by 84 mL ofaqueous sodium dithionate (35.3 mg/mL) was added slowly dropwise over 15min and stirred vigorously until completion. The reaction was dilutedwith EtOAc and washed with 1:1 aq NaHCO₃ and sodium thiosulfate. Theorganic layer was concentrated and purified by flash columnchromatography to afford 1 g of(2R,3R,5S)-5-azido-2-(azidomethyl)-4,4-difluoro-6-hydroxytetrahydro-2H-pyran-3-ylacetate (94% yield).

Step 8(2R,3R,5S,6S)-5-azido-2-(azidomethyl)-4,4-difluoro-6-(2,2,2-trichloro-1-iminoethoxy)tetrahydro-2H-pyran-3-yl acetate

To a solution of 700 mg of(2R,3R,5S)-5-azido-2-(azidomethyl)-4,4-difluoro-6-hydroxytetrahydro-2H-pyran-3-ylacetate in 25 mL of anhydrous DCM was added 720 μL oftrichloroacetonitrile at 0° C. To this solution, 103 μL of DBU wasslowly added at the same temperature. The reaction was stirred untilcompletion at room temperature. The reaction was diluted with DCM andwashed with 1 N HCl, brine and the organic layer was concentrated. Thecrude thus obtained was purified by flash column chromatography (20%EtOAc in hexanes) to afford 750 mg of(2R,3R,5S,6S)-5-azido-2-(azidomethyl)-4,4-difluoro-6-(2,2,2-trichloro-1-iminoethoxy)tetrahydro-2H-pyran-3-ylacetate (75% yield).

Example 15

Step 1(S)—N-[[(2S)-3,4-dihydro-2H-pyran-2-yl]methyl]-2-methyl-propane-2-sulfinamide

To a solution of (NE,S)—N-[[(2S)-3,4-dihydro-2H-pyran-2-yl]methylene]-2-methyl-propane-2-sulfinamide(3.00 g, 13.9 mmol) in ethanol (60.0 mL) at 0° C., was added NaBH₄(0.527 g, 13.9 mmol) and the ice bath was removed and the reactionmixture was stirred 30 min. The reaction was cooled to 0° C. andsaturated NH₄Cl (40.0 mL) was added (CAUTION: gas evolution). Thevolatiles were evaporated under reduced pressure and the residue wasextracted with EtOAc (3×40.0 mL). The combined organic layers were dried(Na₂SO₄), filtered and concentrated under reduced pressure to providethe title compound (3.00 g, 99%) as a solid, which was in the next stepwithout further purification. MS (ESI) [M+H]⁺218.0.

Step 2(S)—N-benzyl-N-[[(2S)-3,4-dihydro-2H-pyran-2-yl]methyl]propane-2-sulfinamide

NaH (60%, 0.635 g, 15.9 mmol) was added to a mixture of(S)—N-[[(2S)-3,4-dihydro-2H-pyran-2-yl]methyl]-2-methyl-propane-2-sulfinamide(3.00 g, 13.8 mmol) and BnBr (2.46 mL, 20.7 mmol) in DMF (10.0 mL) at 0°C. and the reaction mixture was stirred at room temperature for 3 h. Themixture was cooled to 0° C. and then water was added (20.0 mL). Theaqueous layer was extracted with EtOAc (3×25.0 mL) and the combinedorganic layers were washed with water (5×20.0 mL), then dried (Na₂SO₄),filtered and concentrated under reduced pressure. The material waspurified by silica gel chromatography (80 g cartridge) using a gradientof EtOAc and hexane (0-40%) to afford the title compound (4.00 g, 94%)as an oil. MS (ESI) [M+Na]⁺330.2.

Step 3(S)—N-benzyl-N-[[(2S)-5,6-dihydroxytetrahydropyran-2-yl]methyl]-2-methyl-propane-2-sulfinamide

OsO₄ (4% solution in water, 3.91 mL, 0.615 mmol) was added to a solutionof(S)—N-benzyl-N-[[(2S)-3,4-dihydro-2H-pyran-2-yl]methyl]propane-2-sulfinamide(3.78 g, 12.3 mmol) and NMO (2.97 g, 24.6 mmol) in a mixture acetone andH₂O (100 mL, 5:1) at ambient temperature and the reaction mixture wasstirred at room temperature for 3 h. The volatiles were removed underreduced pressure (CAUTION: OsO₄ is volatile) and the residue was dilutedwith saturated solution of sodium thiosulfate (200 mL). The aqueouslayer was then extracted with EtOAc (3×100 mL). The combined organiclayers were dried (Na₂SO₄), filtered and evaporated under reducedpressure. The material was purified by silica gel chromatography (80 gcartridge) using a gradient of EtOAc and hexane (10-50%) as eluent toproduce the title compound (mixture of diastereomers) (4.10 g, 98%) asan oil. MS (ESI) [M+Na]⁺364.9.

Step 4 BenzylN-benzyl-N-[[(2S)-5,6-dihydroxytetrahydropyran-2-yl]methyl]carbamate

Aqueous HCl (1.0 M, 74.4 mL, 72.4 mmol) was dropwise added to a solutionofN-benzyl-N-[[(2S)-5,6-dihydroxytetrahydropyran-2-yl]methyl]-2-methyl-propane-2sulfinamide (4.10 g, 12.0 mmol) in dioxane (100.0 mL) with vigorousstirring. After 1 h, solid Na₂CO₃ (10.2 g, 96.1 mmol) was added. Afteranother 10 min, CbzCl (2.89 mL, 20.3 mmol) was added dropwise and thereaction mixture was stirred for 3 h. The volatiles were evaporated, andthe residue was partitioned in between EtOAc (150 mL) and H₂O (150 mL).The layers were separated, and the organic phase was dried (Na₂SO₄),filtered and concentrated under reduced pressure. The material waspurified by silica gel chromatography (120 g cartridge) using a gradientof ethyl acetate in hexane (0-40%) as eluent to afford the titlecompound (diastereomers, 4.40 g, 99%) as an oil. MS (ESI) [M+Na]⁺394.8.

Step 5[(6S)-2-acetoxy-6-[[benzyl(benzyloxycarbonyl)amino]methyl]tetrahydropyran-3-yl]acetate

To a solution of benzylN-benzyl-N-[[(2S)-5,6-dihydroxytetrahydropyran-2-yl]methyl]carbamate(4.40 g, 11.8 mmol) in a mixture pyridine (10 mL) and DCM (75.0 mL) at0° C., was added acetic anhydride (5.60 mL, 59.2 mmol) and the reactionmixture was stirred at room temperature for 48 h. The mixture wasdiluted with 5% of sulfuric acid (100 mL) and the aqueous layer wasextracted with EtOAc (3×100 mL). The combined organic layers were dried(Na₂SO₄), filtered and concentrated under reduced pressure. The materialwas purified by silica gel chromatography (120 g cartridge) using agradient ethyl acetate of hexane (0-30%) as eluent to afford the titlecompound (diastereomers, 4.90 g, 91%) as an oil. MS (ESI) [M+Na]⁺478.8.

Step 6[(2R,3R,6S)-6-[[benzyl(benzyloxycarbonyl)amino]methyl]-2-[(1R,25,3S,4R,6S)-2,3-diacetoxy-4,6-diazido-cyclohexoxy]tetrahydropyran-3-yl]acetate

A microwave tube was charged with[(6S)-2-acetoxy-6-[[benzyl(benzyloxycarbonyl)amino]methyl]tetrahydropyran-3-yl]acetate(0.70 g, 0.154 mmol),[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-hydroxy-cyclohexyl]acetate(0.504 g, 1.69 mmol) and 4 Å molecular sieves (3.00 g) and then amixture of solvent (DCM/Ether; 5:1, 10.0 mL) was added followed BF₃.Et₂O(0.948 mL, 7.68 mmol). The reaction mixture was stirred at 50° C. for 24h. The mixture was quenched with saturated NaHCO3, and the aqueous layerwas extracted with DCM (3×20.0 mL). The organic combined layers weredried (Na₂SO₄), filtered and concentrated under reduced pressure. Thematerial was purified by silica gel chromatography (180 g) using agradient of ethyl acetate in hexane (0-50%) as eluent to provide thetitle compound (0.750 g, 70%) as mixture of diastereomers. MS (ESI)[M+Na]⁺716.1.

Step 7 BenzylN-benzyl-N-[[(2S,5R,6R)-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]-5-hydroxy-tetrahydropyran-2-yl]methyl]carbamate

NaOMe (25 wt %, 1.59 mL, 5.54 mmol) was added dropwise to a solution of[(2R,3R,6S)-6-[[benzyl(benzyloxycarbonyl)amino]methyl]-2-[(1R,2S,3S,4R,6S)-2,3-diacetoxy-4,6-diazido-cyclohexoxy]tetrahydropyran-3-yl]acetate(0.640 g, 0.923 mmol) in MeOH (25.0 mL) at ambient temperature and thereaction mixture was stirred for 60 min. The mixture was neutralized byAcOH (0.950 mL, 16.6 mmol) and the volatiles were removed under reducedpressure. The material was purified by silica gel chromatography (120 g)using a mixture MeOH (2%) in DCM as eluent to afford the title compound(second eluting, 156 mg, 30%) as an oil. Note: three spots appeared onTLC plate and the middle spot corresponds to the desired diastereomerbenzylN-benzyl-N[[(2S,5R,6R)-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]-5-hydroxy-tetrahydropyran-2-yl]methyl]carbamate.¹H NMR (500 MHz, MeOD) δ 7.55-7.13 (m, 10H), 5.38-5.11 (m, 3H), 4.83(dd, J=15.7, 4.3 Hz, 1H), 4.60 (d, J=15.7 Hz, 1H), 4.39-4.19 (m, 1H),3.76-3.62 (m, 6H), 3.58-3.31 (m, 1H), 3.18 (dt, J=14.2, 7.1 Hz, 1H),2.23 (dt, J=12.8, 4.1 Hz, 1H), 1.99-1.56 (m, 3H), 1.48-1.24 (m, 2H). MS(ESI) [M+Na]⁺590.1.

Step 8[(2R,3R,6S)-2-[(1R,2S,3S,4R,6S)-3-acetoxy-4,6-diazido-2-hydroxy-cyclohexoxy]-6-[[benzyl(benzyloxycarbonyl)amino]methyl]tetrahydropyran-3-yl]acetate

To a solution of benzylN-benzyl-N[[(2S,5R,6R)-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]-5-hydroxy-tetrahydropyran-2-yl]methyl]carbamate(132 mg, 233 μmol) in dry DCM (6.00 mL) at ambient temperature, wasadded Ac₂O (55.0 μL, 581 μmol) and the reaction mixture was stirred for18 h. The volatiles were removed under reduced pressure and the residuewas purified by silica gel chromatography (40 g) using a gradient ofEtOAc in hexane (0-70%) as eluent to provide compound[(2R,3R,4R)-4-acetoxy-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-5-hydroxy-tetrahydrofuran-2-yl]methylacetate (90.0 mg, 61%). MS (ESI) [M+Na]⁺651.9.

Step 9[(2R,3R,4R,5S)-4-acetoxy-5-[(1S,2S,3R,5S,6R)-2-acetoxy-6-[(2R,3R,6S)-3-acetoxy-6-[[benzyl(benzyloxycarbonyl)amino]methyl]tetrahydropyran-2-yl]oxy-3,5-diazido-cyclohexoxy]-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-tetrahydrofuran-2-yl]methylacetate

CCl₃CN (0.212 mL, 2.12 mmol) was added dropwise to a mixture of[(2R,3R,4R)-4-acetoxy-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-5-hydroxy-tetrahydrofuran-2-yl]methylacetate (225 mg, 0.424 mmol) and K₂CO₃ (176 mg, 1.27 mmol) in dry DCM(12.0 mL) at room temperature under N₂. The mixture was stirred at roomtemperature for 18 h, then filtered through Celite and rinsed with dryDCM. The filtrate was concentrated under reduced pressure.

To a solution of[(2R,3R,6S)-2-[(1R,2S,3S,4R,6S)-3-acetoxy-4,6-diazido-2-hydroxy-cyclohexoxy]-6-[[benzyl(benzyloxycarbonyl)amino]methyl]tetrahydropyran-3-yl]acetate(92.0 mg, 0.141 mmol) in DCM (12.0 mL) was added to the above material.4 Å molecular sieves were then added and the mixture was cooled to −10°C. and then BF₃Et₂O (87.1 μL, 0.706 mmol) was added dropwise. Themixture warmed slowly at room temperature and stirred for 5 h. Themixture was diluted with saturated NaHCO₃ (10.0 mL) and the separatedaqueous layer was extracted with DCM (3×20.0 mL). The combined organiclayers were washed with brine, then dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The material was purified by silicagel chromatography (40 g) using gradient of EtOAc in hexane (0-40%) aseluent to provide title product[(2R,3R,4R,5S)-4-acetoxy-5-[(1S,2S,3R,5S,6R)-2-acetoxy-6-[(2R,3R,6S)-3-acetoxy-6-[[benzyl(benzyloxycarbonyl)amino]methyl]tetrahydropyran-2-yl]oxy-3,5-diazido-cyclohexoxy]-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-tetrahydrofuran-2-yl]methylacetate (120 mg, 73%) as an oil. MS (ESI) [M+Na]⁺1186.0.

Step 10 BenzylN-benzyl-N-[[(2S,5R,6R)-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2-[(2S,3R,4S,5R)-4-[(2R,3R,4R,5S,6S)-3-azido-6-(azidomethyl)-4,5-dihydroxy-tetrahydropyran-2-yl]oxy-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]oxy-3-hydroxy-cyclohexoxy]-5-hydroxy-tetrahydropyran-2-yl]methyl]carbamate

NaOMe (25 wt %, 356 μL, 124 μmol) was added dropwise to a solution of[(2R,3R,4R,5S)-4-acetoxy-5-[(1S,2S,3R,5S,6R)-2-acetoxy-6-[(2R,3R,6S)-3-acetoxy-6-[[benzyl(benzyloxycarbonyl)amino]methyl]tetrahydropyran-2-yl]oxy-3,5-diazido-cyclohexoxy]-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-tetrahydrofuran-2-yl]methylacetate (120 mg, 103 μmol) in MeOH (5.00 mL) at ambient temperature andthe reaction mixture was stirred for 1 h. The mixture was neutralized byAcOH (˜118 μL) and the volatiles were removed under reduced pressure.The material was dissolved with EtOAc, filtered through silica gel padand the filtrate was concentrated under reduced pressure to produce thetitle compound (90.0 mg, 96%) as an oil. MS (ESI) [M+Na]⁺934.1.

Step 11 (2S,3S,4R,5R,6R)-5-amino-2-(aminomethyl)-6-[(2R,3S,4R,5S)-5[(1R,2R,3 S,5R,6S)-3,5-diamino-2-[(2R,3R,6S)-6-(aminomethyl)-3-hydroxy-tetrahydropyran-2-yl]oxy-6-hydroxy-cyclohexoxy]-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl]oxy-tetrahydropyran-3,4-diol;formate

Pd(OH)₂/C (20 wt %, 194 mg, 276 μmol) was added to a solution of benzylN-benzyl-N-[[(2S,5R,6R)-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2-[(2S,3R,4S,5R)-4-[(2R,3R,4R,5S,6S)-3-azido-6-(azidomethyl)-4,5-dihydroxy-tetrahydropyran-2-yl]oxy-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]oxy-3-hydroxy-cyclohexoxy]-5-hydroxy-tetrahydropyran-2-yl]methyl]carbamate(42.0 mg, 46.1 μmol) in MeOH (3.60 mL) and EtOH (3.60 mL). H₂ wasbubbled and the suspension was hydrogenated under hydrogen atmospherefor 16 h. The mixture was filtered through a frit (0.22 μm diameter) andthe filtrate was concentrated under reduced pressure. The material waspurified by preparative HPLC to provide the title compound (12.5 mg,43%) as a formate salt. ¹H NMR(400 MHz, MeOD) δ 8.46 (s, 5H), 5.46 (d,J=3.2 Hz, 1H), 5.33 (d, J=2.1 Hz, 1H), 5.22 (s, 1H), 4.57-4.48 (m, 1H),4.32-4.20 (m, 2H), 4.16-4.04 (m, 3H), 3.87-3.52 (m, 7H), 3.41-3.30 (m,2H), 3.13-3.05 (m, 4H), 2.92 (dd, J=13.1, 8.5 Hz, 1H), 2.27 (d, J=11.6Hz, 1H), 1.97-1.61 (m, 4H), 1.43 (dd, J=25.9, 14.0 Hz, 1H). MS (ESI)[M+Na]⁺606.8.

Example 16

Step 1 BenzylN-[(1R)-1-[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]-2-benzyloxy-ethyl]-N-benzyl-carbamate

To a solution of benzylN-[(1R)-1-[(2S,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]-2-benzyloxy-ethyl]-N-benzyl-carbamate(see Example 36 for synthesis, 134 mg, 0.19 mmol) and pyridine (9 μL,1.13 mmol) in dry DCM (5.0 mL) at room temperature was added Ac₂O (9 μL,94 μmol) and the reaction mixture was stirred for 20 h. The volatileswere removed under reduced pressure. The material was purified by MPLCon silica gel (40 g, liquid loading with toluene) using a gradient of0-45% EtOAc in hexane as eluent to provide the title compound (72 mg,96%) as a solid. MS (ESI) [M+H]⁺755.4.

Step 2 Benzyl((R)-1-((2S,5R,6R)-5-azido-6-(((1R,2R,3S,4R,6S)-4,6-diazido-2-(((2S,3R,4S,5R)-4-(((2R,3R,4R,5S,6S)-3-azido-6-(azidomethyl)-4,5-dihydroxytetrahydro-2H-pyran-2-yl)oxy)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)oxy)-3-hydroxycyclohexyl)oxy)tetrahydro-2H-pyran-2-yl)-2-(benzyloxy)ethyl)(benzyl)carbamate

To a mixture of[(2R,3R,4R)-4-acetoxy-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-5-hydroxy-tetrahydrofuran-2-yl]methylacetate (155 mg, 0.29 mmol) and K₂CO₃ (88 mg, 0.64 mmol) in DCM (5.0 mL)was added CCl₃CN (0.08 mL, 0.76 mmol) at room temperature. The mixturewas stirred at room temperature for 18 h, then filtered on Celite,rinsed with DCM and concentrated under reduced pressure. To the abovematerial in dry DCM (20 mL) was added [(1S,2S,3R,4S,6R)-4,6-diazido-3-[(2R,3R,6S)-3-azido-6-[(1R)-1-[benzyl(benzyloxycarbonyl)amino]-2-benzyloxy-ethyl]tetrahydropyran-2-yl]oxy-2-hydroxy-cyclohexyl]acetate(96 mg, 0.13 mmol) followed by activated 3 Å sieves (1 g). The mixturewas cooled to −78° C. and then BF₃.OEt₂ (0.06 mL, 0.51 mmol) was addeddropwise. The acetone-dry ice bath was removed, and the reaction mixturewas slowly warmed to room temperature, and then saturated NaHCO3 (10 mL)was added. The separated aqueous layer was extracted with DCM (3×15 mL).The combined organic layers were washed with brine, dried (MgSO₄),filtered and concentrated under reduced pressure. The residue was takenin MeOH (10 mL) then NaOMe (4.62 M in MeOH, 0.39 mL, 1.78 mmol) wasadded at room temperature and the reaction mixture was stirred for 1 h.The mixture was diluted with saturated NH₄Cl (10 mL) and the separatedaqueous layer was extracted with DCM (3×15 mL). The combined organiclayers were washed with brine, dried (MgSO₄), filtered and concentratedunder reduced pressure. The material was purified by preparative HPLC toprovide the title compound (47 mg, 35%) as a solid. MS (ESI)[M+Na]⁺1079.4.

Step 3(2S,3S,4R,5R,6R)-5-amino-2-(aminomethyl)-6-(((2R,3S,4R,5S)-5-(((1R,2R,3S,5R,6S)-3,5-diamino-2-(((2R,3R,6S)-3-amino-6-((R)-1-amino-2-hydroxyethyl)tetrahydro-2H-pyran-2-yl)oxy)-6-hydroxycyclohexyl)oxy)-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)tetrahydro-2H-pyran-3,4-diol

In a 2 neck flask equipped with a reflux condenser were added benzyl((R)-1-((2S,5R,6R)-5-azido-6-(((1R,2R,3S,4R,6S)-4,6-diazido-2-(((2S,3R,4S,5R)-4-(((2R,3R,4R,5S,6S)-3-azido-6-(azidomethyl)-4,5-dihydroxytetrahydro-2H-pyran-2-yl)oxy)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)oxy)-3-hydroxycyclohexyl)oxy)tetrahydro-2H-pyran-2-yl)-2-(benzyloxy)ethyl)(benzyl)carbamate(43 mg, 0.04 mmol) and Pd/C (10% dry on carbon, 19.5 mg, 0.02 mmol)following by anhydrous MeOH (8 mL). Nitrogen was bubbled for 5 min, thenammonium formate (44 mg, 0.69 mmol) was added. The mixture was heated at63° C. for 5 h under N₂, then cooled to room temperature with anice-bath. The mixture was filtered with a filter syringe andconcentrated under reduced pressure. The material was purified bypreparative HPLC using isocratic 10% B in A (A: Amfor pH 4, B: ACN) onC18 Xbridge 30×150 mm to provide the title compound (22.3 mg, 62%) as asolid. ¹H NMR (500 MHz, MeOD) δ 8.41 (s, 6H), 5.48 (s, 1H), 5.15 (s,1H), 5.09 (d, J=1.5 Hz, 1H), 4.39-4.34 (m, 1H), 4.30-4.17 (m, 3H), 4.103.99 (m, 3H), 3.81-3.71 (m, 3H), 3.68-3.53 (m, 2H), 3.50-3.42 (m, 3H),3.32-3.24 (m, 3H), 3.16-2.99 (m, 3H), 2.26-2.14 (m, 2H), 1.87-1.78 (m,1H), 1.71-1.57 (m, 3H). MS (ESI) [M+H]⁺613.4.

Example 17

Step 1(1S,2R,3R,4S,6R)-4,6-diazido-3-[(2R,3S,4S,5R,6R)-3-azido-6-(azidomethyl)-4-fluoro-5-hydroxy-tetrahydropyran-2-yl]oxy-cyclohexane-1,2-diol

To(2R,3R,4S,5S)-5-azido-2-(azidomethyl)-4-fluoro-6-(2,2,2-trichloro-l-iminoethoxy)tetrahydro-2H-pyran-3-ylacetate (preparation below, 1.00 g, crude) was added[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-hydroxy-cyclohexyl]acetate(500 mg, 1.68 mmol) and grounded 4 Å sieves (3.70 g). Dry DCM (18.0 mL)was added and the suspension was stirred at ambient temperature for 30min. The mixture was cooled to −10° C. and then BF₃Et₂O (1.18 mL, 9.56mmol) was added dropwise with vigorous stirring. The solution was warmedto ambient temperature slowly and stirred for another 5 h. The reactionwas quenched with saturated NaHCO₃ (10.0 mL) and the aqueous layer wasextracted with DCM (3×20.0 mL). The combined organic layers were dried(Na₂SO₄), filtered and concentrated under reduced pressure. The materialwas purified by silica gel chromatography (80 g) using a gradient ofEtOAc in hexane (0-30%) as eluent to provide the title compound as anoil (220 mg, 25%). MS (ESI) [M+Na]⁺576.9.

NaOMe (25 wt %, 686 μL, 2.38 mmol) was added dropwise to a solution of[(1S,2S,3R,4S,6R)-2-acetoxy-3-[(2R,3S,4S,5R,6R)-5-acetoxy-3-azido-6-(azidomethyl)-4-fluoro-tetrahydropyran-2-yl]oxy-4,6-diazido-cyclohexyl]acetate(220 mg, 397 nmol) in MeOH (15.0 mL) at ambient temperature and thereaction mixture was stirred for 60 min. The mixture was neutralizedwith AcOH (408 μL, 7.14 mmol) and the volatiles were removed underreduced pressure. The material was filtered through a silica gel pad andeluted with EtOAc to afford the title compound (165 mg, 97%) as a solid.¹H NMR (500 MHz, MeOD) δ 5.75 (d, J=4.5 Hz, 1H), 5.12 (dt, J=53.8, 2.2Hz, 1H), 4.59 (ddd, J=10.1, 5.1, 2.4 Hz, 1H), 3.72-3.43 (m, 7H), 3.32(t, J=9.5 Hz, 1H), 3.18 (ddd, J=35.0, 4.4, 2.4 Hz, 1H), 2.34 (dt,J=13.0, 4.3 Hz, 1H), 1.50 (dd, J=24.7, 12.3 Hz, 1H).

Step 2[(1S,2S,3R,4S,6R)-3-[(2R,3S,4S,5R,6R)-5-acetoxy-3-azido-6-(azidomethyl)-4-fluoro-tetrahydropyran-2-yl]oxy-4,6-diazido-2-hydroxy-cyclohexyl]acetate

Ac₂O (179 μL, 1.89 mmol) was added to a solution of(1S,2R,3R,4S,6R)-4,6-diazido-3-[(2R,3S,4S,5R,6R)-3-azido-6-(azidomethyl)-4-fluoro-5-hydroxy-tetrahydropyran-2-yl]oxy-cyclohexane-1,2-diol(135 mg, 0.315 mmol) and pyridine (204 μL, 2.52 mmol) in dry DCM (8.0mL) at ambient temperature. The reaction mixture was stirred for 20 hand then the volatiles were removed under reduced pressure. The materialwas purified by silica gel chromatography (40 g cartridge) using agradient of EtOAc in hexane (0-30%) as eluent to afford the titlecompound (126 mg, 78%) as an oil. MS (ESI) [M+Na]⁺535.0.

Step 3(2S,3R,4R,5R,6R)-6-(((2R,3R,4R,5S)-4-acetoxy-5-(((1S,2S,3R,5S,6R)-2-acetoxy-6-(((2R,3S,4S,5R,6R)-5-acetoxy-3-azido-6-(azidomethyl)-4-fluorotetrahydro-2H-pyran-2-yl)oxy)-3,5-diazidocyclohexyl)oxy)-2-(acetoxymethyl)tetrahydrofuran-3-yl)oxy)-5-azido-2-(azidomethyl)tetrahydro-2H-pyran-3,4-diyldiacetate

CCl₃CN (0.370 mL, 3.69 mmol) was added dropwise to a mixture of[(2R,3R,4R)-4-acetoxy-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-5-hydroxy-tetrahydrofuran-2-yl]methylacetate (391 mg, 0.738 mmol) and K₂CO₃ (306 mg, 2.21 mmol) in dry DCM(15.0 mL) at room temperature under N₂. The reaction mixture was stirredat room temperature for 18 h, then filtered through Celite pad andwashed with dry DCM. The filtrate was concentrated under reducedpressure and used in the next step without purification.

To a solution of[(1S,2S,3R,4S,6R)-3-[(2R,3S,4S,5R,6R)-5-acetoxy-3-azido-6-(azidomethyl)-4-fluoro-tetrahydropyran-2-yl]oxy-4,6-diazido-2-hydroxy-cyclohexyl]acetate(126 mg, 0.246 mmol) in dry DCM (15.0 mL), was added the above materialfollowed by molecular sieves 4 Å and the mixture was cooled to −10° C.BF₃.OEt₂ (0.152 mL, 1.23 mmol) was then added dropwise and the reactionmixture was warmed slowly at room temperature and then stirred for 5 h.The mixture was diluted with saturated NaHCO₃ (10.0 mL) and theseparated aqueous layer was extracted with DCM (3×20.0 mL). The combinedorganic layer was washed with brine, then dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The material was purified on silicagel chromatography (40 g cartridge) using a gradient of EtOAc in hexane(0-40%) as eluent to provide the title compound (194 mg, 77%) as asolid. MS (ESI) [M+Na]⁺1047.9.

Step 4(2S,3S,4R,5R,6R)-5-azido-2-(azidomethyl)-6-(((2R,3S,4R,5S)-5-(((1R,2R,3S,5R,6S)-3,5-diazido-2-(((2R,3S,4S,5R,6R)-3-azido-6-(azidomethyl)-4-fluoro-5-hydroxytetrahydro-2H-pyran-2-yl)oxy)-6-hydroxycyclohexyl)oxy)-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)tetrahydro-2H-pyran-3,4-diol

NaOMe (25 wt %, 0.654 mL, 2.27 mmol) was added dropwise to a solution of(2S,3R,4R,5R,6R)-6-(((2R,3R,4R,5S)-4-acetoxy-5-(((1S,2S,3R,5S,6R)-2-acetoxy-6-(((2R,3S,4S,5R,6R)-5-acetoxy-3-azido-6-(azidomethyl)-4-fluorotetrahydro-2H-pyran-2-yl)oxy)-3,5-diazidocyclohexyl)oxy)-2-(acetoxymethyl)tetrahydrofuran-3-yl)oxy)-5-azido-2-(azidomethyl)tetrahydro-2H-pyran-3,4-diyldiacetate (194 mg, 0.189 mmol) in MeOH (6.00 mL) at ambient temperatureand the reaction mixture was stirred for 60 min. The mixture wasneutralized with AcOH (217 μL, 3.79 mmol) and then the volatiles wereremoved under reduced pressure. The material was purified on silica gelpad using EtOAc as eluent to provide the title compound (145 mg, 99%) asa solid. MS (ESI) [M+Na]⁺795.2.

Step 5(2S,3S,4R,5R,6R)-5-amino-2-(aminomethyl)-6-[(2R,3S,4R,5S)-5-[(1R,2R,3S,5R,6S)-3,5-diamino-2-[(2R,3S,4S,5R,6R)-3-amino-6-(aminomethyl)-4-fluoro-5-hydroxy-tetrahydropyran-2-yl]oxy-6-hydroxy-cyclohexoxy]-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl]oxy-tetrahydropyran-3,4-diol

To a solution of(2S,3S,4R,5R,6R)-5-azido-2-(azidomethyl)-6-(((2R,3S,4R,5S)-5-(((1R,2R,3S,5R,6S)-3,5-diazido-2-(((2R,3S,4S,5R,6R)-3-azido-6-(azidomethyl)-4-fluoro-5-hydroxytetrahydro-2H-pyran-2-yl)oxy)-6-hydroxycyclohexyl)oxy)-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)tetrahydro-2H-pyran-3,4-diol(15.0 mg, 19.4 μmol) in THF (2.00 mL) was added trimethylphosphine (777μL, 777 μmol) at ambient temperature and the reaction mixture wasstirred at room temperature for 16 h. The mixture was diluted with water(2.00 mL) and then NaOH (0.3 mL, 0.1 M) were added. The resultingmixture was then stirred for 3 h at ambient temperature, concentratedunder reduced pressure. The material was purified by Sephadex C-25column using water and ammonium hydroxide (0.25%) as eluent to affordthe title compound (6.90 mg, 58%) as a white solid after lyophilization.¹H NMR(400 MHz, MeOD) δ 5.57 (d, J=4.4 Hz, 1H), 5.28 (s, 1H), 4.93 (d,J=1.5 Hz, 1H), 4.75 (d, J=53.4 Hz, 1H), 4.22 (t, J=4.7 Hz, 1H), 4.12(dt, J=8.9, 4.6 Hz, 2H), 3.91 (t, J=3.1 Hz, 1H), 3.85-3.60 (m, 4H), 3.47(dtt, J=28.5, 19.0, 9.4 Hz, 5H), 3.19 (t, J=9.3 Hz, 1H), 3.01 (ddd,J=21.8, 13.4, 5.5 Hz, 3H), 2.90-2.67 (m, 3H), 2.60 (dd, J=16.9, 8.7 Hz,1H), 1.96 (dd, J=8.3, 3.4 Hz, 1H), 1.31-1.16 (m, 1H). MS (ESI)[M+Na]⁺639.1.

Preparation of(2R,3R,4S,5S)-5-azido-2-(azidomethyl)-4-fluoro-6-(2,2,2-trichloro-1-iminoethoxy)tetrahydro-2H-pyran-3-ylacetate

Step 1(4aR,7S,8S,8aR)-7-azido-6-(benzyloxy)-8-fluoro-2-phenylhexahydropyrano[3,2-d][1,3]dioxine

To a solution of 7.7 g of(4aR,7S,8S,8aR)-7-azido-6-(benzyloxy)-8-fluoro-2-phenylhexa-hydropyrano[3,2-d][1,3]dioxinein 60 mL of anhydrous DCM was added 16.1 mL of pyridine and the reactionwas cooled to 0° C. To this solution, 6.8 mL of Triflic anhydride wasadded slowly and the reaction stirred for 1 hour at the sametemperature. After completion, the organic layer was diluted with DCMand washed with 1 N HCl and saturated NaHCO₃. The organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated. Theobtained crude was dissolved in 50 mL, BuOH and 30 mL of toluene and 9.1g of CsF was added and the reaction stirred at 70° C. until completion.The organic layer was diluted with EtOAc and washed with saturatedNaHCO₃, brine and concentrated. The crude was purified by columnchromatography (20% EtOAc in hexanes) to afford 5.5 g of (4aR,7S,8S,8aR)-7-azido-6-(benzyloxy)-8-fluoro-2-phenylhexahydropyrano[3,2-d][1,3]dioxine(72% yield).

Step 2(2R,3R,4S,5S)-5-azido-6-(benzyloxy)-4-fluoro-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol

To a solution of 6.2 g of(4aR,7S,8S,8aR)-7-azido-6-(benzyloxy)-8-fluoro-2-phenylhexahydro-pyrano[3,2-d][1,3]dioxinein 100 mL of MeOH was added 420 mg of p-toluenesulfonic acid at roomtemperature. The reaction was stirred at room temperature untilcompletion (4 hours). The reaction was quenched with 0.1 eq of Et₃N andconcentrated. The crude was purified by flash column chromatography(EtOAc/Hexanes 2:3) to afford 4.5 g of(2R,3R,4S,5S)-5-azido-6-(benzyloxy)-4-fluoro-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol(95% yield).

Step 3(2R,3R,4S,5S)-5-azido-2-(azidomethyl)-6-(benzyloxy)-4-fluorotetrahydro-2H-pyran-3-ol

To a solution of 4.5 g of(2R,3R,4S,5S)-5-azido-6-(benzyloxy)-4-fluoro-2-(hydroxymethyl)tetrahydro-2H-pyran-3-olin anhydrous DCM/pyridine (5:3), 3.75 g of Tosyl Chloride was added at0° C. The reaction was stirred at the same temperature until completion(3 h). The reaction was diluted with 100 mL of DCM and washed with 1 NHCl and aqueous NaHCO₃, dried, filtered and concentrated. The crude wasdissolved in anhydrous DMF and 4.9 g of sodium azide was added. Thereaction was further stirred at 70° C. until completion. DMF wasevaporated and the residue was dissolved in EtOAc and washed with water.The organic layer was dried, filtered, concentrated and purified byflash chromatography to afford 2.9 g of(2R,3R,4S,5S)-5-azido-2-(azidomethyl)-6-(benzyloxy)-4-fluorotetrahydro-2H-pyran-3-ol(60% yield).

Step 4(2R,3R,4S,5S)-5-azido-2-(azidomethyl)-6-(benzyloxy)-4-fluorotetrahydro-2H-pyran-3-ylacetate

(2R,3R,4S,5S)-5-azido-2-(azidomethyl)-6-(benzyloxy)-4-fluorotetrahydro-2H-pyran-3-olwas dissolved in anhydrous pyridine and the solution was cooled to 0° C.Acetic anhydride was slowly added and the reaction was allowed to warmto room temperature and stirred overnight. The reaction was concentratedto dryness, resuspended in EtOAc, and washed with aqueous NaHCO₃ andbrine. The organic portion was dried, filtered, concentrated andpurified by flash chromatography to yield(2R,3R,4S,5S)-5-azido-2-(azidomethyl)-6-(benzyloxy)-4-fluorotetrahydro-2H-pyran-3-ylacetate (89% yield).

Step 5(2R,3R,4S,5S)-5-azido-2-(azidomethyl)-4-fluoro-6-hydroxytetrahydro-2H-pyran-3-ylacetate

1.5 g of(2R,3R,4S,5S)-5-azido-2-(azidomethyl)-6-(benzyloxy)-4-fluorotetrahydro-2H-pyran-3-ylacetate was dissolved in 38 mL of EtOAc. 30 mL of aqueous sodium bromate(0.62 M) was added at once to the EtOAc solution. 60 mL aqueous sodiumdithionate (0.27 M) was added slowly dropwise over 15 min and thereaction was stirred vigorously until completion. The reaction was thendiluted with EtOAc and washed with 1:1 aq NaHCO₃ and sodium thiosulfate.The organic layer was dried, filtered, concentrated and purified byflash column chromatography (30% EtOAc in hexanes) to afford 921 mg of(2R,3R,4S,5S)-5-azido-2-(azidomethyl)-4-fluoro-6-hydroxytetrahydro-2H-pyran-3-ylacetate (82% yield).

Step 6(2R,3R,4S,5S)-5-azido-2-(azidomethyl)-4-fluoro-6-(2,2,2-trichloro-l-iminoethoxy)tetrahydro-2H-pyran-3-yl acetate

To a solution of 950 mg of(2R,3R,4S,5S)-5-azido-2-(azidomethyl)-4-fluoro-6-hydroxytetrahydro-2H-pyran-3-ylacetate in 20 mL of anhydrous DCM was added 970 μL oftrichloroacetonitrile at 0° C. To this solution, 143 μL of DBU wasslowly added at the same temperature. The reaction was stirred untilcompletion at room temperature ( 5 minutes). The reaction was dilutedwith DCM and washed with 1N HCl, brine and the organic layer was dried,filtered and concentrated. The crude thus obtained was purified by flashcolumn chromatography (20% EtOAc in hexanes) to afford 1.04 g of(2R,3R,4S,5S)-5-azido-2-(azidomethyl)-4-fluoro-6-(2,2,2-trichloro-1-iminoethoxy)tetrahydro-2H-pyran-3-yl acetate (78% yield).

Example 18

Step 1(1S,2R,3R,4S,6R)-4,6-diazido-3-[(2S,3R,4R,6R)-3-azido-6-(azidomethyl)-5,5-difluoro-4-hydroxy-tetrahydropyran-2-yl]oxy-cyclohexane-1,2-diol

CCl₃CN (0.34 mL, 3.42 mmol) was added dropwise to a suspension of[(2R,4R,5R)-5-azido-2-(azidomethyl)-3,3-difluoro-6-hydroxy-tetrahydropyran-4-yl]acetate(preparation below, 200 mg, 0.68 mmol) and K₂CO₃ (284 mg, 2.05 mmol) indry DCM (20 mL) at ambient temperature under N₂. After 72 h, thesolution was filtered through cotton and the filtrate was concentratedunder N₂ stream, followed by high-vacuum.

To the above material was added[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-hydroxy-cyclohexyl]acetate(408 mg, 1.37 mmol) and ground 4 Å sieves and then dry DCM (20 mL) wasadded. The suspension was stirred at ambient temperature for 1 h. Thesolution was cooled to −78° C. and BF₃Et₂O (0.34 mL, 2.74 mmol) wasadded dropwise with vigorous stirring and the resulting mixture wasstirred at −78° C. for 1 h. The mixture was warmed to ambienttemperature and stirred for another hour. The reaction was diluted withsaturated NaHCO₃ (100.0 mL) and the aqueous layer mixture was extractedwith DCM (3×50 mL). The combined organic layers were dried (Na₂SO₄),filtered and concentrated under reduced pressure to afford an acetylateddimer.

NaOMe (25 wt %, 0.44 mL, 2.05 mmol) was added dropwise to a solution ofthe crude acetylated dimer in MeOH (2.0 mL) at ambient temperature andthe reaction mixture was stirred for 70 min. The mixture was dilutedwith AcOH (0.23 mL, 4.11 mmol) and the volatiles were removed underreduced pressure. The residue was purified by silica gel chromatography(24 g cartridge) using a gradient of EtOAc in hexane (0-50%) as eluentto afford the title compound (49.5 mg, 16%, 3 steps).

Step 2[(1S,2S,3R,4S,6R)-3-[(2S,3R,4R,6R)-4-acetoxy-3-azido-6-(azidomethyl)-5,5-difluoro-tetrahydropyran-2-yl]oxy-4,6-diazido-2-hydroxy-cyclohexyl]acetate

Ac₂O (62 μL, 659 μmol) was added to a solution of(1S,2R,3R,4S,6R)-4,6-diazido-3-[(2S,3R,4R,6R)-3-azido-6-(azidomethyl)-5,5-difluoro-4-hydroxy-tetrahydropyran-2-yl]oxy-cyclohexane-1,2-diol(49 mg, 110 μmol) and pyridine (71 μL, 878 mmol) in dry DCM (2 mL) atambient temperature and the reaction mixture was stirred for 20 h. Themixture was diluted with MeOH and then the volatiles were removed underreduced pressure. The material was purified by silica gel chromatography(12 g cartridge) using a gradient of EtOAc and hexane (5-25%) as eluentto afford the title compound as an oil along with beta anomer (˜25%).The mixture was repurified by silica gel chromatography (12 g cartridge)using a gradient of EtOAc and hexane (15-30%) as eluent to afford thetitle compound (26.0 mg, 45%) as an oil. ¹H NMR (500 MHz, CDCl₃) δ 5.615.50 (m, 1H), 5.42-5.37 (m, 1H), 4.84 (t, J=9.9 Hz, 1H), 4.46 (ddd,J=24.0, 8.1, 2.9 Hz, 1H), 3.70 (dd, J=10.9, 3.6 Hz, 1H), 3.62 (td,J=9.4, 3.8 Hz, 1H), 3.56-3.32 (m, 7H), 2.38-2.32 (m, 1H), 2.16 (s, 3H),2.11 (s, 3H), 1.65 1.52 (m, 1H).

Step 3(2S,3S,4R,5R,6R)-5-azido-2-(azidomethyl)-6-[(2R,3S,4R,5S)-5-[(1R,2R,3S,5R,6S)-3,5-diazido-2-[(2S,3R,4R,6R)-3-azido-6-(azidomethyl)-5,5-difluoro-4-methyl-tetrahydropyran-2-yl]oxy-6-hydroxy-cyclohexoxy]-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl]oxy-tetrahydropyran-3,4-diol

CCl₃CN (0.074 mL, 0.74 mmol) was added dropwise to a mixture of[(2R,3R,4R)-4-acetoxy-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-5-hydroxy-tetrahydrofuran-2-yl]methylacetate (78 mg, 0.15 mmol) and K₂CO₃ (61 mg, 0.44 mmol) in dry DCM (5mL) at room temperature under N₂. The mixture was stirred at roomtemperature for 18 h, then filtered through a 45 μm nylon filter andrinsed with DCM. The filtrate was concentrated under reduced pressureand used in the next step without further purification.

To a solution of[(1S,2S,3R,4S,6R)-3-[(2S,3R,4R,6R)-4-acetoxy-3-azido-6-(azidomethyl)-5,5-difluoro-tetrahydropyran-2-yl]oxy-4,6-diazido-2-hydroxy-cyclohexyl]acetate(26 mg, 0.049 mmol) in DCM (5 mL) was added the above material followed4 Å molecular sieves and the mixture was cooled to −78° C. BF₃Et₂O(0.030 mL, 0.25 mmol) was then added dropwise and the reaction mixturewas stirred at room temperature for 4 h. The mixture was diluted withsaturated NaHCO₃ (8 mL) and the separated aqueous layer was extractedwith DCM (2×8 mL). The combined organic layer was washed with brine,then dried (Na₂SO₄), filtered and concentrated under reduced pressure.The material was purified by flash column chromatography (12 g) using agradient of EtOAc in hexane (0-45%) as eluent to afford the titlecompound (24.5 mg, 48%). ¹H NMR (500 MHz, CDCl₃) δ 6.04 (d, J=2.6 Hz,1H), 5.57 (ddd, J=19.6, 11.2, 4.6 Hz, 1H), 5.33 (d, J=2.6 Hz, 1H), 5.02(t, J=2.8 Hz, 1H), 4.95 (t, J=9.8 Hz, 1H), 4.92-4.85 (m, 2H), 4.73-4.63(m, 2H), 4.45-4.38 (m, 2H), 4.32-4.25 (m, 2H), 4.10-4.06 (m, 1H), 3.89(t, J=9.0 Hz, 1H), 3.72-3.67 (m, 1H), 3.60-3.40 (m, 5H), 3.33-3.25 (m,3H), 2.40 (dt, J=13.2, 4.5 Hz, 1H), 2.21 (s, 3H), 2.17-2.14 (m, 9H),2.11 (s, 3H), 2.09 (s, 3H), 1.70-1.62 (m, 1H). MS (ESI) [M+NH4]⁺1060.4.

Step 4(2S,3S,4R,5R,6R)-5-azido-2-(azidomethyl)-6-[(2R,3S,4R,5S)-5-[(1R,2R,3S,5R,6S)-3,5-diazido-2-[(2S,3R,4R,6R)-3-azido-6-(azidomethyl)-5,5-difluoro-4-hydroxy-tetrahydropyran-2-yl]oxy-6-hydroxy-cyclohexoxy]-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl]oxy-tetrahydropyran-3,4-diol

NaOMe (25 wt %, 41 μL, 0.14 mmol) was added dropwise to a solution of(2S,3S,4R,5R,6R)-5-azido-2-(azidomethyl)-6-[(2R,3S,4R,5S)-5-[(1R,2R,3S,5R,6S)-3,5-diazido-2-[(2S,3R,4R,6R)-3-azido-6-(azidomethyl)-5,5-difluoro-4-methyl-tetrahydropyran-2-yl]oxy-6-hydroxy-cyclohexoxy]-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl]oxy-tetrahydropyran-3,4-diol(24.5 mg, 0.024 mmol) in MeOH (2 mL) at ambient temperature and thereaction mixture was stirred for 75 min. The mixture was diluted withAcOH (0.013 mL, 0.24 mmol) and the volatiles were removed under reducedpressure. The residue was diluted in EtOAc and the organic layer waswashed with saturated NaHCO₃ and brine, then dried (Na₂SO₄), filteredand concentrated under reduced pressure to give the title compound (18.0mg, 97%). ¹H NMR (500 MHz, MeOD) δ 5.91 (s, 1H), 5.29 (d, J=2.1 Hz, 1H),5.04 (d, J=1.7 Hz, 1H), 4.49-4.36 (m, 1H), 4.31 (dd, J=6.3, 4.7 Hz, 1H),4.21 (dd, J=4.5, 2.2 Hz, 1H), 4.10-4.01 (m, 2H), 3.92 (ddd, J=8.4, 4.5,1.9 Hz, 1H), 3.84 (t, J=3.3 Hz, 1H), 3.78-3.71 (m, 1H), 3.64-3.24 (m,13H), 2.18-2.09 (m, 1H), 1.32-1.25 (m, 1H).

Step 5(2S,3S,4R,5R,6R)-5-amino-2-(aminomethyl)-6-[(2R,3S,4R,5S)-5-[(1R,2R,3S,5R,6S)-3,5-diamino-2-[(2S,3R,4R,6R)-3-amino-6-(aminomethyl)-5,5-difluoro-4-hydroxy-tetrahydropyran-2-yl]oxy-6-hydroxy-cyclohexoxy]-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl]oxy-tetrahydropyran-3,4-diol

Pd(OH)₂ (2.8 mg, 2.0 μmol) was added to a solution of(2S,3S,4R,5R,6R)-5-azido-2-(azidomethyl)-6-[(2R,3S,4R,5S)-5-[(1R,2R,3S,5R,6S)-3,5-diazido-2-[(2S,3R,4R,6R)-3-azido-6-(azidomethyl)-5,5-difluoro-4-hydroxy-tetrahydropyran-2-yl]oxy-6-hydroxy-cyclohexoxy]-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl]oxy-tetrahydropyran-3,4-diol(4.5 mg, 5.7 μmol) in MeOH (3.0 mL) under N₂ at ambient temperature. Thesuspension was bubbled with H₂ for 10 min and then hydrogenated for 16 hunder hydrogen atmosphere (1 atm, balloon). The mixture was filteredthrough a frit (nylon, 0.45 μm diameter), rinsed with MeOH and thefiltrate was concentrated under reduced pressure to give the titlecompound. Note: the exact procedure was repeated (on 13.5 mg, 17.1 μmolscale) to give the title compound (16.4 mg overall amount). ¹H NMR (500MHz, MeOD) δ 5.54 (s, 1H), 5.35 (d, J=2.8 Hz, 1H), 4.98 (d, J=1.7 Hz,1H), 4.43-4.39 (m, 1H), 4.19-4.07 (m, 3H), 4.01-3.93 (m, 3H), 3.86-3.81(m, 1H), 3.74 (dd, J=12.3, 3.9 Hz, 1H), 3.61 (t, J=9.2 Hz, 1H),3.54-3.47 (m, 2H), 3.25 (t, J=9.5 Hz, 1H), 3.15 (dd, J=13.2, 8.4 Hz,1H), 3.06-3.00 (m, 2H), 2.98-2.90 (m, 3H), 2.90-2.84 (m, 1H), 2.68 (ddd,J=12.2, 9.8, 4.1 Hz, 1H), 2.04-1.96 (m, 1H), 1.30-1.20 (m, 1H).

Preparation of[(2R,4R,5R)-5-azido-2-(azidomethyl)-3,3-difluoro-6-hydroxy-tetrahydropyran-4-yl]acetate

Step 1(4aR,7R,8R,8aS)-7-azido-6,8-bis(benzyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxine

To a solution of 4.8 g of(4aR,7R,8R,8aS)-7-azido-6-(benzyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-olin 50 mL of anhydrous DMF at 4° C., was added 750 mg of NaH in severalportions. The reaction was stirred at 0° C. for 30 minutes. 2.2 g ofbenzyl bromide was added to the reaction and the vessel was removed fromthe ice bath and allowed to warm to room temperature. After completion,the reaction was quenched with cold water and concentrated in vacuo. Theconcentrate was dissolved in DCM and washed with equal volumes of 1 NHCl and brine. The organic portion was dried, filtered and concentratedto dryness. The residue was then purified by flash chromatography (10%EtOAc in hexanes) to yield 5.7 g of(4aR,7R,8R,8a5)-7-azido-6,8-bis(benzyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxine(96% yield).

Step 2(2R,3R,4R,5R)-5-azido-2-(azidomethyl)-4,6-bis(benzyloxy)tetrahydro-2H-pyran-3-ol

To a solution of 15 g of(4aR,7R,8R,8aS)-7-azido-6,8-bis(benzyloxy)-2-phenylhexa-hydropyrano[3,2-d][1,3]dioxinein 100 mL of methanol, was added 540 mg of p-toluene sulfonic acid atroom temperature. The reaction was stirred at room temperature for 4hours until completion. The reaction was then quenched with 0.1equivalent of triethylamine, concentrated, and purified by flashchromatography (10% EtOAC in DCM) to yield 5.6 g of the diolintermediate. The diol was dissolved in 15 mL of DCM, cooled to 0° C.,and 9 mL of pyridine was added, followed by 3.6 g of Tosyl chloride. Thereaction was stirred at 0° C. for 3 hours until completion. The reactionwas then diluted with 100 mL of DCM and washed with an equal volume of 1N HCl followed by aqueous sodium bicarbonate. The organic portion wasdried, filtered and concentrated. The crude concentrate was dissolved inmL DMF, 4.7 g of sodium azide was added, and the reaction heated at 70°C. for hours. The DMF was removed by evaporation and the crude wasdissolved in EtOAc and washed with water. The organic portion was dried,filtered, and concentrated then purified by flash chromatography toyield 5.8 g of(2R,3R,4R,5R)-5-azido-2-(azidomethyl)-4,6-bis(benzyloxy)tetrahydro-2H-pyran-3-ol(97% yield).

Step 3 (2R,4R,5R)-5-azido-2-(azidomethyl)-4,6-bis(benzyloxy)dihydro-2H-pyran-3(4H)-one

To a solution of 5.9 g of the alcohol(2R,3R,4R,5R)-5-azido-2-(azidomethyl)-4,6-bis(benzyloxy)tetrahydro-2H-pyran-3-olin 50 mL of DCM was added 1.57 g of NaHCO₃ and 7.93 g of DMP at 0° C.and the reaction was allowed to warm to room temperature and stirreduntil completion. The reaction was quenched with aqueous sodiumbicarbonate, diluted with DCM, and washed with an equal volume ofaqueous sodium bicarbonate. The organic portion was dried, filtered,concentrated, and purified by flash chromatography to yield a whitesolid. The solid was washed with Et₂O to obtain 5.0 g of pure product(85% yield).

Step 4(2R,4R,5R)-5-azido-2-(azidomethyl)-4,6-bis(benzyloxy)-3,3-difluorotetrahydro-2H-pyran

To a solution of 2.6 g of(2R,4R,5R)-5-azido-2-(azidomethyl)-4,6-bis(benzyloxy)dihydro-2H-pyran-3(4H)-onein 30 mL DCM was added 3.5 g of DAST and 291 mg HF/pyridine at 0° C. Thereaction was then heated to reflux until the reaction was complete. Thereaction was then cooled to 0° C. and quenched with aqueous sodiumbicarbonate, then diluted with DCM and washed with an equal volume ofaqueous sodium bicarbonate. The organic portion was dried, filtered andconcentrated, then purified by flash chromatography (15:85EtOAc/Hexanes) to yield 1.8 grams of(2R,4R,5R)-5-azido-2-(azidomethyl)-4,6-bis(benzyloxy)-3,3-difluorotetrahydro-2H-pyran(66% yield).

Step 5(3R,4R,6R)-3-azido-6-(azidomethyl)-5,5-difluorotetrahydro-2H-pyran-2,4-diyldiacetate

The starting material,(2R,4R,5R)-5-azido-2-(azidomethyl)-4,6-bis(benzyloxy)-3,3-difluorotetrahydro-2H-pyran,was dissolved in 7.2 mL EtOAc. 6 mL of aqueous sodium bromate (69 mM)was added to the reaction in one portion. Next, aqueous sodiumdithionate was slowly added dropwise over 15 minutes and the reactionstirred vigorously until completion. The reaction was diluted with EtOAcand and washed with 1:1 aqueous sodium bicarbonate and sodiumthiosulfate. The organic layer was concentrated and dissolved in 10 mLanhydrous pyridine. 3 mL of acetic anhydride was added slowly and thereaction stirred at room temperature until completion. The reaction wasconcentrated to dryness, dissolved in 100 mL DCM, and washed with 1 NHCl aq, followed by saturated aqueous sodium bicarbonate. The organicportion was concentrated, dissolved in DCM, and purified by flashchromatography (3:7 EtOAc/Hexanes) to yield 135 mg of(3R,4R,6R)-3-azido-6-(azidomethyl)-5,5-difluorotetrahydro-2H-pyran-2,4-diyldiacetate (88% yield).

Step 6(2R,4R,5R)-5-azido-2-(azidomethyl)-3,3-difluoro-6-hydroxytetrahydro-2H-pyran-4-ylacetate

To a solution of 140 mg(3R,4R,6R)-3-azido-6-(azidomethyl)-5,5-difluorotetrahydro-2H-pyran-2,4-diyldiacetate in 2 mL of anhydrous DMF, was added 40 mg of hydrazineacetate. The reaction was heated at 50° C. for 1 hour. The reaction wasconcentrated to dryness and the residue taken up in 100 mL DCM. Theorganic layer was washed with 1 N HCl and aqueous sodium bicarbonate.The washed organic portion was concentrated and purified by flashchromatography (3:7 EtOAc/Hexanes). 110 mg of(2R,4R,5R)-5-azido-2-(azidomethyl)-3,3-difluoro-6-hydroxytetrahydro-2H-pyran-4-ylacetate was isolated (92% yield).

Example 19

Step 1 Benzyl N-[[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2-hydroxy-3-methoxy-cyclohexoxy]tetrahydropyran-2-yl]methyl]-N-benzyl-carbamate

Me₂SO₄ (128 μL, 1.35 mmol) was added to a vigorously stirring suspensionof benzylN-[[(5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]methyl]-N-benzyl-carbamate(see Example 21 for synthesis, 100 mg, 169 μmol) and TBAI (9 mg, 25μmol) in DCM (2.5 mL) and NaOH solution (1.0 M aq., 2.5 mL, 2.5 mmol) atambient temperature. After 2 h, concentrated NH₄OH (300 μL) was addedand the mixture was partitioned in between water (10.0 mL) and DCM (10.0mL). The aqueous layer was extracted with DCM (2×5.0 mL). The combinedorganic layers were dried (Na₂SO₄), filtered and concentrated underreduced pressure. The residue was filtered through silica gel (0.30 g)and eluted with EtOAc (6.0 mL). The filtrate was concentrated underreduced pressure and the material was purified by preparative HPLC (BEH30×150 mm C18 ACN/AmForm 70-80%) to provide the title compound(rotamers, 72 mg, 70%) as a solid. ¹H NMR (500 MHz, CDCl₃) δ 7.39-7.13(m, 10H), 5.34-5.08 (m, 3H), 4.81-4.69 (m, 1H), 4.56-4.45 (m, 1H), 4.27(d, J=43.5 Hz, 1H), 3.69 (s, 3H), 3.61-3.14 (m, 8H), 2.99 (t, J=9.5 Hz,1H), 2.22 (dt, J=13.2, 4.5 Hz, 1H), 2.08-1.96 (m, 1H), 1.96-1.87 (m,1H), 1.87-1.68 (m, 1H), 1.50-1.30 (m, 2H). MS ESI [M+H]⁺607.3.

Step 2[(2R,3R,4R,5S)-4-acetoxy-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-5-[(1R,2R,3S,5R,6S)-3,5-diazido-2-[(2R,3R,6S)-3-azido-6-[[benzyl(benzyloxycarbonyl)amino]methyl]tetrahydropyran-2-yl]oxy-6-methoxy-cyclohexoxy]tetrahydrofuran-2-yl]methylacetate

CCl₃CN (119 μL, 1.19 mmol) was added dropwise to a suspension of[(2R,3R,4R)-4-acetoxy-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-5-hydroxy-tetrahydrofuran-2-yl]methylacetate (126 mg, 237 μmol) and K₂CO₃ (98 mg, 712 μmol) in dry DCM (2.0mL) at ambient temperature under N₂. After 18 h, the solution wasfiltered through cotton and the filtrate was concentrated under N₂stream, followed by high-vacuum. To the crude material was added asolution of benzylN-[[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2-hydroxy-3-methoxy-cyclohexoxy]tetrahydropyran-2-yl]methyl]-N-benzyl-carbamate(72 mg, 119 μmol) in DCM (3.0 mL) and then all volatiles were evaporatedunder N₂ stream. To the mixture was added ground 4 Å sieves (500 mg) andthe mixture was dissolved in dry DCM (2.0 mL). The suspension wasstirred at ambient temperature for 60 min, then cooled to 0° C., andthen BF₃.OEt₂ (43 μL, 351 μmol) was added. The mixture was stirred atambient temperature for 1 h and then Et₃N (200 μL) was added. Themixture was filtered through a silica gel pad (0.50 g) and eluted withEtOAc (10.0 mL). The volatiles were evaporated under reduced pressureand the material was purified by reversed phase chromatography (C18, 30g cartridge) with ACN and 0.1% aqueous formic acid (50-100%) to producethe title compound (105 mg, 79%) as a solid. MS ESI [M+H]⁺1019.4.

Step 3 BenzylN-[[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2-[(2S,3R,4S,5R)-4-[(2R,3R,4R,5S,6S)-3-azido-6-(azidomethyl)-4,5-dihydroxy-tetrahydropyran-2-yl]oxy-3-hydroxy-5-thydroxymethyl)tetrahydrofuran-2-yl]oxy-3-methoxy-cyclohexoxy]tetrahydropyran-2-yl]methyl]-N-benzyl-carbamate

NaOMe (25 wt %, 77 μL, 336 μmol) was added dropwise to a solution of[(2R,3R,4R,5S)-4-acetoxy-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-5-[(1R,2R,35,5R,6S)-3,5-diazido-2-[(2R,3R,6S)-3-azido-6-[[benzyl(benzyloxycarbonyl)amino]methyl]tetrahydropyran-2-yl]oxy-6-methoxy-cyclohexoxy]tetrahydrofuran-2-yl]methylacetate (47 mg, 42 μmol) in MeOH (1.0 mL) at ambient temperature and thereaction mixture was stirred for 75 min. AcOH (29 μL, 504 μmol) wasadded dropwise and all volatiles were evaporated under reduced pressure.The material was filtered through silica gel (0.30 g) and eluted withEtOAc (8.0 mL) to provide the title compound (rotamers, 39 mg, 98%) as asolid. ¹H NMR (500 MHz, CDCl₃) δ 7.39-7.25 (m, 9H), 7.18 (d, J=7.1 Hz,1H), 5.73 (d, J=25.1 Hz, 1H), 5.40 (d, J=4.6 Hz, 1H), 5.30-5.07 (m, 3H),4.85-4.65 (m, 1H), 4.59-4.46 (m, 1H), 4.39-4.22 (m, 2H), 4.16 (s, 1H),4.11-4.08 (m, 1H), 4.02 (ddd, J=8.5, 4.5, 1.9 Hz, 1H), 3.99 (dd, J=5.8,4.8 Hz, 1H), 3.88 (dd, J=12.6, 2.3 Hz, 1H), 3.83-3.73 (m, 3H), 3.69-3.60(m, 4H), 3.52 (t, J=9.5 Hz, 1H), 3.47-3.33 (m, 5H), 3.28-3.13 (m, 1H),3.12-2.88 (m, 3H), 2.23-2.15 (m, 1H), 2.15-2.09 (m, 1H), 1.93-1.69 (m,2H).

Step 4(2S,3S,4R,5R,6R)-5-amino-2-(aminomethyl)-6-[(2R,3S,4R,5S)-5-[(1R,2R,3S,5R,6S)-3,5-diamino-2-[(2R,3R,6S)-3-amino-6-(aminomethyl)tetrahydropyran-2-yl]oxy-6-methoxy-cyclohexoxy]-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl]oxy-tetrahydropyran-3,4-dio1,2,2,3,3,4,4,4-heptafluorobutanoicacid

Pd(OH)₂/C (10 wt %, 18 mg, 13 μmol) was added to a solution of benzylN-[[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2-[(2S,3R,4S,5R)-4-[(2R,3R,4R,5S,6S)-3-azido-6-(azidomethyl)-4,5-dihydroxy-tetrahydropyran-2-yl]oxy-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]oxy-3-methoxy-cyclohexoxy]tetrahydropyran-2-yl]methyl]-N-benzyl-carbamate(18 mg, 19 μmol) in 4:1 AcOH/H₂O (0.50 mL) under N₂ at ambienttemperature. H₂ was bubbled into the solution for 20 min and theresulting mixture was for 20 h. The mixture was filtered through a frit(0.45 μm diameter), washed with water (5.0 mL) and the filtrate waslyophilized. The material was purified by a HFBA-coupled preparativeHPLC to provide the title compound (4.4 mg, 12%) as a solid. ¹H NMR (500MHz, MeOD) δ 6.08 (d, J=3.5 Hz, 1H), 5.40 (d, J=3.9 Hz, 1H), 5.32 (d,J=1.3 Hz, 1H), 4.40 (t, J=5.7 Hz, 1H), 4.29 (dd, J=6.0, 4.1 Hz, 1H),4.24 (t, J=9.5 Hz, 1H), 4.16-4.07 (m, 4H), 3.95 (t, J=8.9 Hz, 1H), 3.90(dd, J=12.2, 2.4 Hz, 1H), 3.76 (dd, J=12.1, 5.3 Hz, 1H), 3.69-3.67 (m,1H), 3.67 (s, 3H), 3.56-3.46 (m, 3H), 3.41-3.35 (m, 3H), 3.26 (dd,J=13.4, 3.9 Hz, 1H), 3.15 (dd, J=13.2, 2.4 Hz, 1H), 2.95 (dd, J=13.2,8.6 Hz, 1H), 2.46 (dt, J=12.1, 3.7 Hz, 1H), 2.23-2.08 (m, 2H), 1.96-1.83(m, 2H), 1.57-1.46 (m, 1H). MS (ESI) [M+H]⁺597.4.

Example 20

Step 1 BenzylN-[[(2S,5R,6R)-5-azido-6-[(1R,2S,3R,4R,5S,6R)-2,4-diazido-3,5,6-trihydroxy-cyclohexoxy]tetrahydropyran-2-yl]methyl]-N-benzyl-carbamate

To a suspension of benzylN-[[(2S,5R)-5-azido-6-hydroxy-tetrahydropyran-2-yl]methyl]-N-benzyl-carbamate(see Example 11 for synthesis, 101 mg, 0.26 mmol) and K₂CO₃ (155 mg,1.12 mmol) in DCM (3 mL) was added CCl₃CN (0.14 mL, 1.40 mmol). Themixture was stirred at room temperature for 18 h, then filtered onCelite, rinsed with DCM and concentrated under reduced pressure.[(1S,2R,3S,4S,5R,6R)-3,4-diacetoxy-2,6-diazido-5-hydroxy-cyclohexyl]acetate(70 mg, 0.20 mmol) was added to the above material, and the mixture wasco-evaporated with anhydrous toluene (3×10 mL) and then was dried underreduced pressure for 2 h. To a solution of above material in anhydrousEt₂O (10 mL) were added activated 3 Å (0.5 g) and 4 Å sieves (0.5 g).The mixture was stirred at room temperature for 1 h, then cooled to −45°C. TMSOTf (0.01 mL, 0.06 mmol) was added dropwise and the mixture wasstirred at −40° C. for 2 h, then warmed to room temperature. A saturatedsolution of NaHCO₃ (20 mL) was added and the separated aqueous layer wasextracted with EtOAc (3×30 mL). The combined organic layers were dried(MgSO₄), filtered and concentrated under reduced pressure. To a solutionof above material in MeOH (6 mL), NaOMe (4.62 M in MeOH, 0.34 mL, 1.57mmol) was added and the mixture was stirred at room temperature for 1 h.The volatiles were evaporated under reduced pressure. The residue wasdissolved in DCM (25 mL) and a saturated solution of NH₄Cl (25 mL) wasadded. The separated aqueous layer was extracted with DCM (2×30 mL). Thecombined organic layers were dried (MgSO₄), filtered and concentratedunder reduced pressure. The material was purified by MPLC on silica (24g, liquid loading with toluene) using a gradient of 0-50% EtOAc inhexane as eluent to provide the title compound (70 mg, 59% over 3 steps)as a solid. MS (ESI) [M+H]⁺609.2

Step 2[(1S,2R,3S,4S,5R,6S)-3-acetoxy-2,6-diazido-5-[(2R,3R,6S)-3-azido-6-[[benzyl(benzyloxycarbonyl)amino]methyl]tetrahydropyran-2-yl]oxy-4-hydroxy-cyclohexyl]acetate

To a solution of benzylN-[[(2S,5R,6R)-5-azido-6-[(1R,2S,3R,4R,5S,6R)-2,4-diazido-3,5,6-trihydroxy-cyclohexoxy]tetrahydropyran-2-yl]methyl]-N-benzyl-carbamate(70 mg, 0.115 mmol) in DCM (3 mL) was added pyridine (0.07 mL, 0.81mmol) followed by Ac₂O (0.07 mL, 0.69 mmol) and the reaction mixture wasstirred at room temperature for 18 h. MeOH (1 mL) was then added and themixture was concentrated under reduced pressure. The material waspurified by MPLC on silica gel (24 g, liquid loading with toluene) usinga gradient of 0-45% EtOAc in hexane as eleunt to provide the titlecompound (45 mg, 57%) as a solid.

Step 3 Benzyl(((2S,5R,6R)-5-azido-6-(((1R,2S,3R,4R,5S,6R)-2,4-diazido-6-(((2S,3R,4S,5R)-4-(((2R,3R,4R,5S,6S)-3-azido-6-(azidomethyl)-4,5-dihydroxytetrahydro-2H-pyran-2-yl)oxy)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)oxy)-3,5-dihydroxycyclohexyl)oxy)tetrahydro-2H-pyran-2-yl)methyl)(benzyl)carbamate

To a mixture of[(2R,3R,4R)-4-acetoxy-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-5-hydroxy-tetrahydrofuran-2-yl]methylacetate (76 mg, 0.14 mmol) and K₂CO₃ (54 mg, 0.07 mmol) in DCM (10 mL)was added CCl₃CN (0.05 mL, 0.52 mmol) at room temperature. The mixturewas stirred at room temperature for 18 h, then filtered on Celite,rinsed with DCM and concentrated under reduced pressure. To the abovematerial in dry DCM (10 mL) was added(1S,2R,3S,4S,5R,6S)-2,4-diazido-5-4(2R,3R,6S)-3-azido-6-((benzyl((benzyloxy)carbonyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-6-hydroxycyclohexane-1,3-diyldiacetate (45 mg, 0.07 mmol) followed by activated 3 Å sieves (1 g).

The mixture was cooled to −78° C. and then BF₃.OEt₂ (0.03 mL, 0.23 mmol)was added dropwise. The acetone-dry ice bath was removed, and thereaction mixture was slowly warmed to room temperature, and thensaturated NaHCO₃ (10 mL) was added. The separated aqueous layer wasextracted with DCM (3×15 mL). The combined organic layers were washedwith brine, dried (MgSO₄), filtered and concentrated under reducedpressure. To a solution of the above material in MeOH (10 mL), NaOMe(4.62 M in MeOH, 0.14 mL, 0.65 mmol) was added at room temperature andthe reaction mixture was stirred for 1 h. The mixture was diluted withsaturated NH₄Cl (10 mL) and the separated aqueous layer was extractedwith DCM (3×15 mL). The combined organic layers were washed with brine,dried (MgSO₄), filtered and concentrated under reduced pressure. Thematerial was purified by preparative HPLC to provide the title compound(18 mg, 29% over 3 steps) as a solid. MS (ESI) [M+Na]⁺953.3.

Step 4(2S,3S,4R,5R,6R)-5-amino-2-(aminomethyl)-6-(((2R,3S,4R,5S)-5-(((1R,2R,3S,4R,5R,6S)-3,5-diamino-2-(((2R,3R,6S)-3-amino-6-(aminomethyl)tetrahydro-2H-pyran-2-yl)oxy)-4,6-dihydroxycyclohexyl)oxy)-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)tetrahydro-2H-pyran-3,4-diol;6 HCOOH

MeOH (5.0 mL) was added to a mixture of Pd/C (10% on carbon, 8.0 mg,0.01 mmol) and benzyl(((2S,5R,6R)-5-azido-6-(((1R,2S,3R,4R,5S,6R)-2,4-diazido-6-(((2S,3R,4S,5R)-4-(((2R,3R,4R,5S,6S)-3-azido-6-(azidomethyl)-4,5-dihydroxytetrahydro-2H-pyran-2-yl)oxy)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)oxy)-3,5-dihydroxycyclohexyl)oxy)tetrahydro-2H-pyran-2-yl)methyl)(benzyl)carbamate(18 mg, 0.02 mmol) under N₂. The suspension was degassed for 5 min, thenammonium formate (18 mg, 0.28 mmol) was added. The septum was replacedby a reflux condenser, followed by 3 vacuum/nitrogen cycles and thereaction mixture was heated at 63° C. for 5 h, then cooled to roomtemperature. The mixture was filtered with a syringe filter andconcentrated under reduced pressure. The material was purified bypreparative HPLC (Waters) (Bridge C18, 30×150 mm; 40 mL/min) usingisocratic 10% acetonitrile in water (10 mM AmForm pH 3.8) over 7 min toprovide the title compound (6.60 mg, 40%) as a solid. ¹H NMR (500 MHz,D₂O) δ 8.47 (br, 6H), 5.91 (d, J=3.3 Hz, 1H), 5.44 (d, J=2.5 Hz, 1H),5.33 (s, 1H), 4.51 (t, J=5.5 Hz, 1H), 4.42-4.39 (m, 1H), 4.36-4.33 (m,1H), 4.28-4.18 (m, 3H), 4.05-3.91 (m, 3H), 3.87-3.84 (m, 1H), 3.80-3.71(m, 3H), 3.64-3.61 (m, 1H), 3.60-3.55 (m, 1H), 3.49-3.38 (m, 2H),3.34-3.23 (m, 3H), 3.11 (dd, J=13.5, 7.6 Hz, 1H), 2.12-1.99 (m, 2H),1.98-1.91 (m, 1H), 1.66-1.55 (m, 1H). MS (ESI) [M+H]⁺599.4.

Example 21

Step 1(3aR,5R,6S,6aS)-5-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-6-fluoro-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxole

Allofuranose diacetonide (10 g, 38.4 mmol) was dissolved in 35 mL of dryDCM and pyridine at −78° C. To the cold solution, 2.7 M Deoxyfluor intoluene (20 mL, 54 mmol) was added dropwise. The reaction was stirredfor 7 days at 40° C. The reaction was quenched with sat NaHCO₃, and theaqueous phase was extracted with DCM (3×50 mL). Combined organic phaseswere washed with NaHCO₃ (100 mL) and dried with Na₂SO₄. The crudematerial was purified by MPLC to afford the title compound (9.54 g, 36.4mmol, 95%). Acetonides fragment on mass spec: MS (ESI) M—bothacetonides+=205.1.

Step 2 [(2R)-2-[(3aR,5R,6 S,6aS)-6-fluoro-2,2-dimethyl-3a,5,6,6a-tetrahy drofuro[2,3-d][1,3]dioxol-5-yl]-2-acetoxy-ethyl]acetate;[(2R,3R,4S,5S)-3,5,6-triacetoxy-4-fluoro-tetrahydropyran-2-yl]methylacetate

Fluorinated allofuranose diacetonide (9.5 g, 36.2 mmol) was dissolved in10 mL of THF and 100 mL of 5% TFA in water was added to the solution.The reaction was stirred for 14 hours at room temperature. The solutionwas rotovaped and co-evaporated with toluene (100 mL). Then dissolved in40 mL of acetic anhydride and refluxed for 30 min with 6 equiv (1.3 g)of sodium acetate. After that the reaction was cooled to roomtemperature. and quenched with sat NaHCO₃/CH₂Cl₂=300 mL/300 mL twice.The organic phase was washed with brine and aqueous phase was backwashedwith EtOAc 300 mL. Combined org phases were dried over Na₂SO₄ andreduced to an oil which was purified by MPLC to afford the titlecompound (7.66 g, 11.7 mmol, 60%) MS (ESI) [M+NH₄]⁺=368.1.

Step 3[(2R,3R,4S,5R,6S)-3,5-diacetoxy-4-fluoro-6-phenylsulfanyl-tetrahydropyran-2-yl]methylacetate

3-deoxy-3-fluoro-allopyranose tetracetate (7.7 g, 22.0 mmol) andthiophenol (4.85 g, 4.50 mmol) were dissolved in DCM (100 mL) with 10 gof activated 4 Å molecular sieves and stirred for at least 24 hours atroom temperature under dry nitrogen. The suspension was treated withBF₃Et₂O and the reaction suspension was stirred overnight. The crudematerial was purified by MPLC to afford the title compound (2.5 g, 6.24mmol, 28%) MS (ESI) [M+NH₄]⁺=418.2.

Step 4(2R,3R,4S,5R,6S)-4-fluoro-2-(hydroxymethyl)-6-phenylsulfanyl-tetrahydropyran-3,5-diol

1-phenylthio-3-deoxy-3-fluoro-allopyranoside peracetate (2.5 g, 6.24mmol) was dissolved in 25 mL of 4:1=MeOH:DCM mixture and treated with 5mL of 25% NaOMe in MeOH. The reaction was stirred for 1 h at roomtemperature. The reaction was quenched with Amberlyst 15 resin which wasfiltered and washed with 20 mL of MeOH, solvent was evaporated and thecrude material was used in the next step without any furtherpurification. MS (ESI) [M+NH₄]⁺=292.3.

Step 5[(2R,3R,4S,5R,6S)-4-fluoro-3,5-dihydroxy-6-phenylsulfanyl-tetrahydropyran-2-yl]methyl4-methylbenzenesulfonate

1-phenylthio-3-deoxy-3-fluoro-allopyranoside (2.28 g, 8.31 mmol) wasdissolved in 5 mL of DCM at 0° C. and Et₃N (4.20 g, 41.6 mmol) with TsCl(1.91 g, 10 mmol) were added sequentially. After 3 hours the crudereaction in DCM was purified by MPLC to afford the title compound (1.92g, 4.62 mmol, 38%) MS (ESI) [M+NH₄]⁺=446.1.

Step 6(2R,3R,4S,5R,6S)-2-(azidomethyl)-4-fluoro-6-phenylsulfanyl-tetrahydropyran-3,5-diol

1-phenylthio-3-deoxy-3-fluoro-6-OTs-allopyranoside (1.98 g, 4.62 mmol)was dissolved in 17 mL of DMF and NaN₃ (0.36 g, 5.54 mmol) was added.The reaction was stirred at 80° C. for 5 hours. The reaction was washedwith NaHCO₃ (7 mL) and extracted with EtOAc (3×10 mL) and the combinedorganic phases were washed with brine, and dried with Na₂SO₄. The crudewas used in the next step without further purification (1.36 g, 4.54mmol, 98%).

Step 7(2R,3R,4S,5R,6S)-2-(azidomethyl)-3,5-dibenzyloxy-4-fluoro-6-phenylsulfanyl-tetrahydropyran

1-phenylthio-3-deoxy-3-fluoro-6-azido-allopyranoside (1.36 g, 4.54 mmol)and BnBr (2.33 g, 13.6 mmol) were dissolved in 16 mL of DMF withcatalytic TBAI (0.18 g, 0.45 mmol). Dry NaH (0.44 g, 18.2 mmol) wasadded to the mixture at 0° C. The reaction was stirred at roomtemperature for 3 hours after which the reaction was quenched with 5 MNH₄Cl and extracted with Et2O (3×100 mL), which washed with brine. Thecrude was purified by MPLC to provide the title compound (1.37 g, 2.86mmol, 63%) MS (ESI) [M+Na]⁺=497.2.

Step 8[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-[(2R,3S,4S,5R,6R)-6-(azidomethyl)-3,5-dibenzyloxy-4-fluoro-tetrahydropyran-2-yl]oxy-cyclohexyl]acetate

1-phenylthio-3-deoxy-3-fluoro-6-N₃-allopyranoside and1,3-N₃-5,6-Ac-2-DOS were coevaporated with toluene (3×5 mL) and dried inhigh vacuum, were dissolved in DCM (12 mL) with 2 g of activated 4 Å molsieves. The suspension was stirred at room temperature for 14 hours andcooled to −78° C. followed by a quick addition of NIS (dried in highvacuum for 12 hours). The reaction was allowed to stir for 30 min at−78° C. and catalytic TfOH was added. The reaction was stirred at −78°C. for 1 hour and allowed to warm up to room temperature over 2 hours.The reaction turned to dark brown-purple color. TLC showed productformation with R_(f)˜0.55 in 20% EtOAc in hexanes as a single spot. Thereaction was quenched with Et₃N and filtered and the molecular sieveswere washed on filter with 50 mL of DCM. Organic phase was washed with30 mL of sat. NaHCO₃ and 50 mL of water. Aqueous phases were dried withNa₂SO₄ and crude after concentration was taken up in 3 mL of DCM andpurified by MPLC to afford the title compound (0.82 g, 1.23 mmol, 88%.MS (ESI) [M+Na]⁺=690.3.

Step 9[(1S,2S,3R,4S,6R)-4,6-diazido-3-[(2R,3S,4S,5R,6R)-6-(azidomethyl)-3,5-dibenzyloxy-4-fluoro-tetrahydropyran-2-yl]oxy-2-hydroxy-cyclohexyl]acetate

NaOMe (25 wt %, 518 μL, 1.80 mmol) was added dropwise to a solution of[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-[(2R,3S,4S,5R,6R)-6-(azidomethyl)-3,5-dibenzyloxy-4-fluoro-tetrahydropyran-2-yl]oxy-cyclohexyl]acetate(200 mg, 300 μmol) in MeOH (15.0 mL) at ambient temperature and thereaction mixture was stirred for 60 min. The mixture was neutralizedwith AcOH (308 μL, 5.39 mmol) and the volatiles were removed underreduced pressure. The material was purified through a silica gel plugusing EtOAc as eluent to afford the title compound, which was used inthe next without further purification. MS (ESI) [M+Na]⁺606.9.

Ac₂O (162 μL, 1.72 mmol) was added to a solution of(1S,2R,3R,4S,6R)-4,6-diazido-3-[(2R,3 S,4S,5R,6R)-6-(azidomethyl)-3,5-dibenzyloxy-4-fluoro-tetrahydropyran-2-yl]oxy-cyclohexane-1,2-diol(167 mg, 0.286 mmol) and pyridine (185 μL, 2.29 mmol) in dry DCM (10.0mL) at ambient temperature and the reaction mixture was stirred for 16h. The volatiles were removed under reduced pressure and the materialwas purified by silica gel chromatography (40 g cartridge) using agradient of EtOAc in hexane (0-30%) as eluent to afford the titlecompound (128 mg, 70%) as an oil. MS (ESI) [M+Na]⁺648.1.

Step 10[(2R,3R,4R,5S)-4-acetoxy-5-[(1S,2S,3R,5S,6R)-2-acetoxy-3,5-diazido-6-[(2R,3S,4S,5R,6R)-6-(azidomethyl)-3,5-dibenzyloxy-4-fluoro-tetrahydropyran-2-yl]oxy-cyclohexoxy]-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-tetrahydrofuran-2-yl]methylacetate

CCl₃CN (0.308 mL, 3.07 mol) was added dropwise to a mixture of[(2R,3R,4R)-4-acetoxy-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-5-hydroxy-tetrahydrofuran-2-yl]methylacetate (326 mg, 0.614 mmol) and K₂CO₃ (254 mg, 1.84 mmol) in dry DCM(15.0 mL) at room temperature under N₂. The reaction mixture was stirredat room temperature for 18 h, then filtered through a Celite pad, washedwith dry DCM and the filtrate was concentrated under reduced pressure.

To a solution of(((1S,2S,3R,4S,6R)-4,6-diazido-3-[(2R,3S,4R,5R,6R)-6-(azidomethyl)-3,5-dibenzyloxy-4-fluoro-tetrahydropyran-2-yl)oxy-2-hydroxy-cyclohexyl]acetate(128 mg, 0.205 mmol) in DCM (15.0 mL) was added the above materialfollowed molecular sieves 4 Å were added and the mixture was cooled to−10° C. BF₃.OEt₂ (0.126 mL, 1.02 mmol) was then added dropwise and themixture was warmed slowly at room temperature and stirred for 4 h. Themixture was diluted with saturated NaHCO₃ (10.0 mL) and the separatedaqueous layer was extracted with DCM (3×20.0 mL). The combined organiclayer was washed with brine, then dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The material was purified on silicagel chromatography (40 cartridge) using a gradient of EtOAc in hexane(0-40%) as eluent to provide the title compound (213 mg, 92%) as an oil.¹H NMR (400 MHz, CDCl₃) δ 7.45-7.26 (m, 10H), 5.83 (t, J=3.5 Hz, 1H),5.26 (s, 1H), 5.08-5.01 (m, 2H), 4.99 (d, J=4.5 Hz, 1H), 4.95-4.86 (m,3H), 4.85 (d, J=1.8 Hz, 1H), 4.77 (q, J=11.2 Hz, 2H), 4.72-4.67 (m, 1H),4.61 (d, J=11.3 Hz, 1H), 4.46 (dd, J=12.1, 2.4 Hz, 1H), 4.41 (dd, J=7.5,4.6 Hz, 1H), 4.27-4.04 (m, 5H), 3.79-3.24 (m, 12H), 2.31 (dt, J=13.2,4.6 Hz, 1H), 2.17 (s, 6H), 2.07 (s, 3H), 2.04 (s, 3H), 1.58 (dd, J=24.7,12.3 Hz, 1H). MS (ESI) [M+Na]⁺1161.3.

Step 11(2S,3S,4R,5R,6R)-5-azido-2-(azidomethyl)-6-[(2R,3S,4R,5S)-5-[(1R,2R,3S,5R,6S)-3,5-diazido-2-[(2R,3S,4S,5R,6R)-6-(azidomethyl)-3,5-dibenzyloxy-4-fluoro-tetrahydropyran-2-yl]oxy-6-hydroxy-cyclohexoxy]-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl]oxy-tetrahydropyran-3,4-diol

NaOMe (25 wt %, 0.647 mL, 2.25 mmol) was added dropwise to a solution of[(2R,3R,4R,5S)-4-acetoxy-5-[(1S,2S,3R,5S,6R)-2-acetoxy-3,5-diazido-6-[(2R,3S,4S,5R,6R)-6-(azidomethyl)-3,5-dibenzyloxy-4-fluoro-tetrahydropyran-2-yl]oxy-cyclohexoxy]-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-tetrahydrofuran-2-yl]methylacetate (213 mg, 0.187 mmol) in MeOH (10.0 mL) at ambient temperatureand the reaction mixture was stirred for 60 min. The mixture wasneutralized by adding AcOH (214 μL, 3.74 mmol) and the volatiles wereremoved under reduced pressure. The material was purified on silica plugusing EtOAc as eluent to provide the title compound (155 mg, 89%) as asolid. ¹H NMR (500 MHz, MeOD) δ 7.73-7.22 (m, 10H), 6.22 (t, J=3.5 Hz,1H), 5.39 (d, J=1.9 Hz, 1H), 5.15 (d, J=1.8 Hz, 1H), 5.07-4.91 (m, 3H),4.76 (d, J=11.2 Hz, 1H), 4.68 (d, J=11.4 Hz, 1H), 4.44 (dd, J=6.5, 4.5Hz, 1H), 4.35 (dd, J=4.5, 1.9 Hz, 1H), 4.20 (td, J=6.2, 2.8 Hz, 2H),4.04 (ddd, J=8.2, 4.8, 2.0 Hz, 1H), 3.99 (t, J=3.4 Hz, 1H), 3.88 (dd,J=11.9, 2.8 Hz, 1H), 3.83-3.76 (m, 1H), 3.75-3.54 (m, 8H), 3.53-3.40 (m,5H), 2.26-2.15 (m, 1H), 1.37 (m, 1H). MS (ESI) [M+Na]⁺950.8.

Step 12(2S,3S,4R,5R,6R)-5-amino-2-(aminomethyl)-6-[(2R,3S,4R,5S)-5-[(1R,2R,3S,5R,6S)-3,5-diamino-2-[(2R,3S,4S,5R,6R)-6-(aminomethyl)-4-fluoro-3,5-dihydroxy-tetrahydropyran-2-yl]oxy-6-hydroxy-cyclohexoxy]-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl]oxy-tetrahydropyran-3,4-diol

Pd(OH)₂ (20 wt %, 109 mg, 155 μmol) was added to a solution of(2S,3S,4R,5R,6R)-5-azido-2-(azidomethyl)-6-[(2R,3S,4R,5S)-5-[(1R,2R,3S,5R,6S)-3,5-diazido-2-[(2R,3S,4S,5R,6R)-6-(azidomethyl)-3,5-dibenzyloxy-4-fluoro-tetrahydropyran-2-yl]oxy-6-hydroxy-cyclohexoxy]-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl]oxy-tetrahydropyran-3,4-diol(24.0 mg, 25.9 μmol) in a mixture MeOH (2.00 mL) and EtOH (2.00 mL). H₂was bubbled for 5 min and the suspension was hydrogenated for 16 h. Themixture was filtered through a frit (0.22 μm diameter) and the filtratewas concentrated under reduced pressure. The material was purified bypreparative HPLC to provide(2S,3S,4R,5R,6R)-5-amino-2-(aminomethyl)-6-[(2R,3S,4R,5S)-5-[(1R,2R,3S,5R,6S)-3,5-diamino-2-[(2R,3S,4S,5R,6R)-6-(aminomethyl)-4-fluoro-3,5-dihydroxy-tetrahydropyran-2-yl]oxy-6-hydroxy-cyclohexoxy]-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl]oxy-tetrahydropyran-3,4-diol(13.4 mg, 15%) as HFBA salt. ¹H NMR(400 MHz, MeOD) δ 5.67 (t, J=3.5 Hz,1H), 5.37 (d, J=2.4 Hz, 1H), 5.25 (d, J=1.6 Hz, 1H), 4.60 (dt, J=52.2,8.2 Hz, 1H), 4.52-4.46 (m, 1H), 4.29 (dd, J=4.9, 2.4 Hz, 1H), 4.27-4.21(m, 1H), 4.17-4.09 (m, 3H), 3.98 (ddd, J=10.2, 6.7, 3.9 Hz, 1H), 3.85(dd, J=15.0, 5.8 Hz, 1H), 3.81-3.71 (m,3H), 3.69-3.47 (m, 4H), 3.43-3.30(m, 2H), 3.25-3.08 (m, 4H), 2.49-2.35 (m, 1H), 1.91 (dd, J=25.0, 12.5Hz, 1H). MS (ESI) [M+H]⁺618.4.

Example 22

Step 1[(2R,3S,4R,5R,6R)-5-azido-2-(azidomethyl)-4,6-difluoro-tetrahydropyran-3-yl]4-nitrobenzoate

CCl₃CN (241 μL, 2.40 mmol) was added dropwise to a suspension of[(2R,3S,4R,5S)-5-azido-2-(azidomethyl)-4-fluoro-6-hydroxy-tetrahydropyran-3-yl]4-nitrobenzoate (preparation below, 183 mg, 480 μmol) and K₂CO₃ (199 mg,1.44 mmol) in dry THF (2.0 mL) at ambient temperature under N₂ and thereaction mixture was stirred for 18 h. The mixture was filtered throughcotton and the filtrate was concentrated under N₂ stream, and then driedunder high-vacuum. To the above material was added[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-hydroxy-cyclohexyl]acetate(2-DOS, 179 mg, 600 μmol) and ground 4 Å sieves (750 mg) and the mixturewas dissolved in dry DCM (2.5 mL). The suspension was stirred at ambienttemperature for 60 min. The mixture was cooled to 0° C. and BF₃.OEt₂(237 μL, 1.92 mmol) was added dropwise with vigorous stirring. Thereaction mixture was warmed to ambient temperature and stirred foranother 60 min. The reaction was quenched with saturated NaHCO₃ (5.0 mL)and the aqueous layer was extracted with DCM (3×5.0 mL). The combinedorganic layers were dried (Na₂SO₄), filtered and concentrated underreduced pressure. The material was purified by silica gel chromatography(25 g cartridge) using a gradient of with EtOAc and hexane (5-50%) aseluent to provide the title compound (60 mg, 19%) as a solid. ¹H NMR(500 MHz, CDCl₃) δ 8.34 (d, J=9.0 Hz, 2H), 8.24 (d, J=9.0 Hz, 2H),5.92-5.85 (m, 1H), 5.31 (t, J=4.2 Hz, 1H), 5.22-5.05 (m, 2H), 4.96 (t,J=10.0 Hz, 1H), 4.64 (t, J=5.9 Hz, 1H), 3.84 (td, J=10.2, 3.9 Hz, 1H),3.73-3.61 (m, 2H), 3.57-3.45 (m, 2H), 3.31 (dd, J=13.0, 5.3 Hz, 1H),2.46 (dt, J=13.4, 4.6 Hz, 1H), 2.12 (s, 3H), 2.10 (s, 3H), 1.65 (dd,J=25.9, 12.5 Hz, 1H).

Step 2(1S,2R,3R,4S,6R)-4,6-diazido-3-[(2R,3S,4R,5S,6R)-3-azido-6-(azidomethyl)-4-fluoro-5-hydroxy-tetrahydropyran-2-yl]oxy-cyclohexane-1,2-diol

NaOMe (25 wt %, 138 μL, 605 μmol) was added dropwise to a solution of[(2R,3S,4R,5S,6R)-5-azido-2-(azidomethyl)-6-[(1R,2S,3S,4R,6S)-2,3-diacetoxy-4,6-diazido-cyclohexoxy]-4-fluoro-tetrahydropyran-3-yl]4-nitrobenzoate (80 mg, 121 μmol) in MeOH (1.0 mL) at ambienttemperature. The solution was warmed to 50° C. and stirred for 60 min.The solution was cooled to ambient temperature and the volatiles wereevaporated under reduced pressure. The residue was diluted withsaturated NaHCO₃ (5.0 mL) and DCM (5.0 mL). The separated aqueous layerwas extracted with DCM (5.0 mL). The combined organic layers were dried(Na₂SO₄), filtered and concentrated under reduced pressure. The materialwas purified by C18 reverse phase chromatography (12 g cartridge) usinga gradient of ACN and 0.1% formic acid (10-45%) to provide the titlecompound (30 mg, 53%) as a solid. ¹H NMR (500 MHz, CDCl₃) δ 5.34 (t,J=4.2 Hz, 1H), 4.93 (ddd, J=49.4, 10.1, 3.2 Hz, 1H), 4.31-4.21 (m, 2H),4.12 (td, J=10.4, 3.8 Hz, 1H), 3.84 (s, 1H), 3.63 (dd, J=12.3, 6.6 Hz,1H), 3.53-3.37 (m, 4H), 3.35-3.26 (m, 2H), 2.87 (s, 1H), 2.39 (s, 1H),2.36-2.26 (m, 1H), 1.57-1.46 (m, 1H). MS (ESI) [M−H]⁻427.3.

Step 3[(1S,2S,3R,4S,6R)-3-[(2R,3S,4R,5S,6R)-5-acetoxy-3-azido-6-(azidomethyl)-4-fluoro-tetrahydropyran-2-yl]oxy-4,6-diazido-2-hydroxy-cyclohexyl]acetate

Ac₂O (17 μL, 180 μmol) was added to a solution of(1S,2R,3R,4S,6R)-4,6-diazido-3-[(2R,3S,4R,5S,6R)-3-azido-6-(azidomethyl)-4-fluoro-5-hydroxy-tetrahydropyran-2-yl]oxy-cyclohexane-1,2-diol(17 mg, 40 μmol) and pyridine (32 μL, 397 μmol) in dry DCM (1.0 mL) atambient temperature and the reaction mixture was stirred for 18 h. MeOH(100 μL) was added and the volatiles were evaporated under reducedpressure. The material was purified by C18 reverse phase chromatography(4 g cartridge) using a gradient of ACN and 0.1% aq formic acid (20-70%)to provide the title compound (12 mg, 59%) as a solid. ¹H NMR (500 MHz,CDCl₃) δ 5.64-5.54 (m, 1H), 5.41 (t, J=4.2 Hz, 1H), 5.08-4.89 (m, 2H),4.37 (dd, J=6.9, 5.4 Hz, 1H), 4.01 (td, J=10.3, 3.8 Hz, 1H), 3.65 (dd,J=11.7, 5.3 Hz, 2H), 3.52 (ddd, J=12.5, 10.0, 4.6 Hz, 1H), 3.48-3.38 (m,2H), 3.34 (ddd, J=12.2, 10.0, 4.5 Hz, 1H), 3.25 (dd, J=12.9, 5.1 Hz,1H), 2.38 (dt, J=13.3, 4.5 Hz, 1H), 2.19 (s, 3H), 2.18 (s, 3H),1.64-21.56 (m, 1H).

Step 4[(2R,3R,4R,5S)-4-acetoxy-5-[(1S,2S,3R,5S,6R)-2-acetoxy-6-[(2R,3S,4R,5S,6R)-5-acetoxy-3-azido-6-(azidomethyl)-4-fluoro-tetrahydropyran-2-yl]oxy-3,5-diazido-cyclohexoxy]-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-tetrahydrofuran-2-yl]methylacetate

CCl₃CN (94 μL, 940 μmol) was added dropwise to a suspension of[(2R,3R,4R)-4-acetoxy-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-5-hydroxy-tetrahydrofuran-2-yl]methylacetate (99 mg, 187 μmol) and K₂CO₃ (78 mg, 562 μmol) in dry DCM (1.5mL) at ambient temperature under N₂ and the reaction mixture was stirredfor 18 h. The mixture was filtered through a Celite pad and the filtratewas concentrated under N₂ stream, and then dried under high-vacuum. Tothe above material was added[(1S,2S,3R,4S,6R)-3-[(2R,3S,4R,5S,6R)-5-acetoxy-3-azido-6-(azidomethyl)-4-fluoro-tetrahydropyran-2-yl]oxy-4,6-diazido-2-hydroxy-cyclohexyl]acetate(48 mg, 94 μmol) in DCM (3.0 mL) and the volatiles were evaporated underN₂ stream. To the mixture was added ground 4 Å sieves (300 mg) followedby dry DCM (1.5 mL). The suspension was stirred at ambient temperaturefor 90 min, then cooled to 0° C. BF₃.OEt₂ (92 μL, 749 μmol) was addedand the reaction mixture was stirred at ambient temperature for another1 h. Et₃N (200 μL) was added and the mixture was filtered through asilica gel pad (0.30 g) and eluted with EtOAc. The filtrate wasevaporated under reduced pressure and the material was purified by C18reversed phase chromatography (12 g cartridge) using a gradient of ACNand 0.1% aq. formic acid (50-100%) as eluent to afford the titlecompound (63 mg, 66%) as a solid. ¹H NMR (500 MHz, CDCl₃) δ 6.05 (t,J=4.0 Hz, 1H), 5.56 (dd, J=5.7, 3.6 Hz, 1H), 5.34 (d, J=2.5 Hz, 1H),5.03-4.86 (m, 5H), 4.73-4.66 (m, 1H), 4.49-4.39 (m, 3H), 4.33-4.28 (m,1H), 4.24 (dd, J=12.2, 4.9 Hz, 1H), 4.09 (ddd, J=8.0, 4.4, 1.7 Hz, 1H),3.87 (t, J=9.0 Hz, 1H), 3.70-3.65 (m, 1H), 3.65-3.55 (m, 2H), 3.49 (ddd,J=12.6, 9.9, 4.5 Hz, 1H), 3.45-3.36 (m, 2H), 3.34-3.29 (m, 1H), 3.28(dd, J=13.0, 4.4 Hz, 1H), 3.21 (dd, J=12.9, 4.2 Hz, 1H), 2.35 (dt,J=13.2, 4.5 Hz, 1H), 2.17 (s, 3H), 2.16 (s, 3H), 2.15 (s, 3H), 2.15 (s,3H), 2.12 (s, 3H), 2.11 (s, 3H), 1.59 (dd, J=25.7, 12.7 Hz, 1H). MS(ESI) [M+NH₄]⁺1042.2.

Step 5(2S,3S,4R,5R,6R)-5-azido-2-(azidomethyl)-6-[(2R,3S,4R,5S)-5-[(1R,2R,3S,5R,6S)-3,5-diazido-2-[(2R,3S,4R,5S,6R)-3-azido-6-(azidomethyl)-4-fluoro-5-hydroxy-tetrahydropyran-2-yl]oxy-6-hydroxy-cyclohexoxy]-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl]oxy-tetrahydropyran-3,4-diol

NaOMe (25 wt %, 141 μL, 615 μmol) was added dropwise to a solution of[(2R,3R,4R,5S)-4-acetoxy-5-[(1S,2S,3R,5S,6R)-2-acetoxy-6-[(2R,3S,4R,5S,6R)-5-acetoxy-3-azido-6-(azidomethyl)-4-fluoro-tetrahydropyran-2-yl]oxy-3,5-diazido-cyclohexoxy]-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-tetrahydrofuran-2-yl]methylacetate (63 mg, 62 μmol) in MeOH (2.0 mL) at ambient temperature and thereaction mixture was stirred for 90 min. AcOH (53 μL, 922 μmol) wasadded and the volatiles were evaporated under reduced pressure. Thematerial was filtered through silica gel (0.50 g) and eluted with EtOAc(10.0 mL). The filtrate was concentrated under reduced pressure toprovide the title compound (46 mg, 97%) as a solid, which was used inthe next step without further purification. MS (ESI) [M+NH₄]⁺790.3.

Step 6(2S,3S,4R,5R,6R)-5-amino-2-(aminomethyl)-6-[(2R,3S,4R,5S)-5-[(1R,2R,3S,5R,6S)-3,5-diamino-2-[(2R,3S,4R,5S,6R)-3-amino-6-(aminomethyl)-4-fluoro-5-hydroxy-tetrahydropyran-2-yl]oxy-6-hydroxy-cyclohexoxy]-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl]oxy-tetrahydropyran-3,4-diol,formic acid

Pd(OH)₂/C (10 wt %, 7.6 mg, 5.4 μmol) was added to a solution of(2S,3S,4R,5R,6R)-5-azido-2-(azidomethyl)-6-[(2R,3 S,4R,5S)-5-[(1R,2R,3S,5R,6S)-3,5-diazido-2-[(2R,3S,4R,5S,6R)-3-azido-6-(azidomethyl)-4-fluoro-5-hydroxy-tetrahydropyran-2-yl]oxy-6-hydroxy-cyclohexoxy]-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl]oxy-tetrahydropyran-3,4-diol(21 mg, 27 μmol) in MeOH (3.0 mL) under N₂ at ambient temperature. H₂was bubbled into the solution for 15 min and then the suspension washydrogenated under hydrogen atmosphere for 18 h. The mixture wasfiltered through a frit (0.45 μm diameter) and then formic acid (40 μL)was added to the filtrate. The filtrate was concentrated under reducedpressure and then lyophilization to provide the title compound(hexa-formate salt, 20.5 mg, 82%) as a solid. ¹H NMR (500 MHz, MeOD) δ8.49 (s, 6H), 6.01 (t, J=4.2 Hz, 1H), 5.41 (d, J=2.1 Hz, 1H), 5.27 (d,J=1.5 Hz, 1H), 5.09 (ddd, J=49.5, 10.9, 3.0 Hz, 1H), 4.51 (dd, J=6.7,4.7 Hz, 1H), 4.40-4.33 (m, 2H), 4.30 (ddd, J=4.7, 3.4, 0.8 Hz, 1H), 4.22(dd, J=8.5, 1.9 Hz, 1H), 4.20-4.17 (m, 1H), 4.16 (t, J=3.1 Hz, 1H),3.94-3.86 (m, 2H), 3.82 (t, J=9.5 Hz, 1H), 3.78-3.71 (m, 2H), 3.69-3.66(m, 1H), 3.56-3.50 (m, 1H), 3.43-3.40 (m, 1H), 3.40-3.33 (m, 2H),3.26-3.13 (m, 4H), 2.31 (dt, J=12.5, 4.2 Hz, 1H), 1.79-1.68 (m, 1H). MS(ESI) [M+H]⁺617.51.

Preparation of[(2R,3S,4R,5S)-5-azido-2-(azidomethyl)-4-fluoro-6-hydroxy-tetrahydropyran-3-yl]4-nitrobenzoate

Step 1(2R,3S,4R,5S)-5-azido-2-(azidomethyl)-6-(benzyloxy)-4-fluorotetrahydro-2H-pyran-3-yl4-nitrobenzoate

To a solution of 4.52 g of DIAD in 30 mL of THF was added 5.13 g oftriphenylphosphine at 0° C. and stirred for 1 h at the same temperature.To this solution, was added p-nitrobenzoic acid at the same temperatureand stirred for 1 hour. To this solution,(2R,3R,4R,5S,6R)-5-azido-2-(azidomethyl)-6-(benzyloxy)-4-fluorotetrahydro-2H-pyran-3-olin 30 mL of anhydrous THF was slowly added at 0° C. and the reactionallowed to reach room temperature. The reaction mixture was stirreduntil completion of the reaction. The reaction was purified by flashchromatography (30% EtOAc in Hexanes) to afford 1.85 g of(2R,3S,4R,5S)-5-azido-2-(azidomethyl)-6-(benzyloxy)-4-fluorotetrahydro-2H-pyran-3-yl4-nitrobenzoate (74% yield).

Step 2(2R,3S,4R,5S)-5-azido-2-(azidomethyl)-4-fluoro-6-hydroxytetrahydro-2H-pyran-3-yl4-nitrobenzoate

To a solution of 2 g of(2R,3S,4R,5S)-5-azido-2-(azidomethyl)-6-(benzyloxy)-4-fluorotetrahydro-2H-pyran-3-yl4-nitrobenzoate in EtOAc was added 3 g of NaBrO₃ dissolved in 30 mL ofwater. To this mixture, 3.14 g sodium dithionate dissolved in 60 mL ofwater was added over 30 min. The reaction mixture was vigorously stirreduntil completion (3-6 h). The organic layer was separated and washedwith 200 mL of 1:1 mixture of aqueous sodium thiosulfate (5%) andsaturated aqueous NaHCO₃. The organic layer was dried over anhydroussodium sulfate and concentrated. The obtained crude was purified byflash chromatography (EtOAc/Hexanes 1:3) to afford 1 g of(2R,3S,4R,5S)-5-azido-2-(azidomethyl)-4-fluoro-6-hydroxytetrahydro-2H-pyran-3-yl4-nitrobenzoate (63% yield).

Example 23

Step 1(R)—N-[(1S,2R)-2-(benzenesulfonyl)-1-[(2S)-3,4-dihydro-2H-pyran-2-yl]-2-fluoro-ethyl]-2-methyl-propane-2-sulfinamide

To a solution of(NE,R)-N-[[(2S)-3,4-dihydro-2H-pyran-2-yl]methylene]-2-methyl-propane-2-sulfinamide(4.82 g, 22.4 mmol) and fluoromethylsulfonylbenzene (3.90 g, 22.4 mmol)in anhydrous THF (100 mL), at −78° C. was added LiHMDS (1.00 M in THF,23.5 mL, 23.5 mmol) and the reaction mixture was stirred at −78° C. for1 h. The mixture was warmed to 20° C. and quenched with saturated NaHCO₃(50 mL). The mixture was diluted with EtOAc (150 mL) and water (100 mL).The separated organic phase was dried (Na₂SO₄), filtered and concertedunder reduced pressure. The material was purified by columnchromatography on silica gel (120 g, dry pack) using a gradient of20-50% EtOAc in hexane as eluent to afford the title compound (7.84 g,90%, 1:1 mixture). MS (ESI) [M+Na]⁺412.3.

Step 2(R)—N-[(1S)-1-[(2S)-3,4-dihydro-2H-pyran-2-yl]-2-fluoro-ethyl]-2-methyl-propane-2-sulfinamide

To a solution of(R)—N-[(1S)-2-(benzenesulfonyl)-1-[(2S)-3,4-dihydro-2H-pyran-2-yl]-2-fluoro-ethyl]-2-methyl-propane-2-sulfinamide(8.4 g, 21.6 mmol) in MeOH (75 mL), was added Mg (2.10 g, 86 mmol) in 4portions over 1 h (bubbles) and the reaction mixture was stirredovernight at room temperature. The mixture was concentrated underreduced pressure and then saturated NH₄Cl and Et₂O was added. Theseparated organic phase was washed with brine (100 mL), then dried(Na₂SO₄), filtered and concentrated under reduced pressure to providetitle product(R)—N-[(1S)-1-[(2S)-3,4-dihydro-2H-pyran-2-yl]-2-fluoro-ethyl]-2-methyl-propane-2-sulfinamide(3.65 g, 68%). ¹H NMR (400 MHz, CDCl₃) δ 6.31-6.26 (m, 1H), 4.67 (tdd,J=6.3, 3.1, 2.0 Hz, 1H), 4.54 (dd, J=4.9, 1.4 Hz, 1H), 4.42 (dd, J=4.9,1.3 Hz, 1H), 3.98 (dd, J=10.2, 5.5 Hz, 1H), 3.68 (d, J=8.3 Hz, 1H),3.59-3.45 (m, 1H), 2.08 1.91 (m, 3H), 1.76 1.63 (m, 1H), 1.18 (s, 9H).MS (ESI) [M+H]⁺250.4.

Step 3(R)—N-benzyl-N-[(1S)-1-[(2S)-3,4-dihydro-2H-pyran-2-yl]-2-fluoro-ethyl]-2-methyl-propane-2-sulfinamide

To a solution of(R)—N-[(1S)-1-[(2S)-3,4-dihydro-2H-pyran-2-yl]-2-fluoro-ethyl]-2-methyl-propane-2-sulfinamide(3.65 mg, 14.6 mmol) and benzyl bromide (2.61 mL, 22.0 mmol) in DMF (30mL) at 0° C., was added sodium hydride (60.0%, 703 mg, 17.6 mmol) andthe reaction mixture was stirred at 20° C. for 1 h. The mixture wasquenched with brine (100 mL) and the aqueous layer was extracted withEtOAc (150 mL). The organic phase was dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The material was purified by columnchromatography on silica gel (120 g) using a gradient of 0-40% EtOAc inhexane as eluent to afford the title compound (2.76 g, 56%). MS (ESI)[M+Na]⁺362.4.

Step 4Benzyl-N-benzyl-N-[(1S)-2-fluoro-1-[(2S)-6-hydroxy-5-iodo-tetrahydropyran-2-yl]ethyl]carbamate

To a suspension of(R)—N-benzyl-N-[(1S)-1-[(2S)-3,4-dihydro-2H-pyran-2-yl]-2-fluoro-ethyl]-2-methyl-propane-2-sulfinamide(2.78 g, 8.19 mmol) and NaHCO₃ (2.06 g, 24.6 mmol) in a mixture of ACN(30 mL) and H₂O (30 mL) at 0° C., was added 12 (3.12 g, 12.3 mmol)portionwise and the reaction mixture was stirred at 20° C. for 90 min.The mixture was diluted with saturated aqueous solution of Na₂S₂O₃ (100mL) and the aqueous layer was extracted with EtOAc (100 mL). The organiclayer was dried (Na₂SO₄), filtered, and concentrated under reducedpressure to provide the iodolactol. MS (ESI) [M+Na]⁺506.2.

To a solution of above material (3.96 g, 8.19 mmol) in dioxane (100 mL)with vigorous stirring, was added 1.0 M aqueous HCl (32.8 mL, 32.8 mmol)and the reaction mixture was stirred for 1 h. Solid Na₂CO₃ (6.94 g, 65.5mmol) was then added and the mixture was stirred for 10 min. CbzCl (1.63mL, 11.5 mmol) was added dropwise and the reaction mixture was stirredfor 30 min. The mixture was partitioned in between EtOAc (50 mL) and H₂O(50 mL). The aqueous layer was extracted with EtOAc (50 mL) and thecombined organic layers were combined were dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The material was purified by columnchromatography on silica gel (120 g) using a gradient of 0-55% EtOAc inhexane as eluent to provide the title compound (3.30 g, 79%). MS (ESI)[M+Na]⁺536.2.

Step 5 BenzylN-[(1S)-1-[(2S)-5-azido-6-oxo-tetrahydropyran-2-yl]-2-fluoro-ethyl]-N-benzyl-carbamate

To a solution of benzylN-benzyl-N-[(1S)-2-fluoro-1-[(2S)-6-hydroxy-5-iodo-tetrahydropyran-2-yl]ethyl]carbamate(3.30 g, 6.43 mmol) in DCM (200 mL), was added 4 Å molecular sieves(2.00 g) followed by PDC (10.9 g, 28.9 mmol) and the suspension wasstirred for 18 h. The mixture was filtered on a silica pad, rinsed withEtOAc and concentrated under reduced pressure. The residue material wasdissolved in DMF (30 mL) and then cooled at 0° C. NaN₃ (0.46 g, 7.07mmol) was added and the reaction mixture was stirred for 1 h at roomtemperature. The mixture was diluted with brine (250 mL) and theseparated aqueous layer was extracted with Et₂O. The combined organiclayers were dried over (Na₂SO₄), filtered and concentrated under reducedpressure to provide the title compound as a mixture of diastereomers(1.9 g, 69%), which was used in the next step without furtherpurification. MS (ESI) [M+Na]⁺449.3.

Step 6 BenzylN-[(1S)-1-[(2S,5R)-5-azido-6-hydroxy-tetrahydropyran-2-yl]-2-fluoro-ethyl]-N-benzyl-carbamate

DIBAL-H (1 M in toluene, 8.96 mL, 8.96 mmol) was added dropwise to asolution of benzylN-[(1S)-1-[(2S)-5-azido-6-oxo-tetrahydropyran-2-yl]-2-benzyloxy-ethyl]-N-benzyl-carbamate(1.91 g, 4.48 mmol) in DCM (50 mL) at −78° C. and the reaction mixturewas stirred at room temperature for 1 h. EtOH (1 mL) was added dropwiseand the mixture was poured into a saturated aqueous solution ofRochelle's salt (300 mL) and then was stirred vigorously stirred for 1h. The separated aqueous layer was extracted with DCM (2×75 mL). Thecombined organic layer was washed with brine, then dried (Na₂SO₄),filtered and concentrated under reduced pressure. The material waspurified flash chromatography on silica gel (120 g) using a gradient of25-70% Et₂O in hexane to provide benzylN-[(1S)-1-[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]-2-fluoro-ethyl]-N-benzyl-carbamate(first eluting, 489 mg, 26%) and a diastereomer (second eluting, 283 mg,15%). MS (ESI) [M+Na]⁺451.1. (5.69 and 5.86 min are the first elutingdiastereomer; 5.57 and 5.78 min are the first eluting diastereomer).

Step 7(1S,2R,3R,4S,6R)-4,6-diazido-3-[(2R,3R,6S)-3-azido-6-[(1S)-1-[benzyl(methyl)amino]-2-fluoro-ethyl]tetrahydropyran-2-yl]oxy-cyclohexane-1,2-diol

To a suspension of benzylN-[(1S)-1-[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]-2-fluoro-ethyl]-N-benzyl-carbamate(150 mg, 0.58 mmol) and K₂CO₃ (174 mg, 1.26 mmol) in DCM (5 mL) under N₂was added CCl₃CN (0.20 mL, 2.01 mmol). The mixture was stirred at roomtemperature for 66 h, then the filtered through Celite, rinsed with DCMand concentrated under reduced pressure.

[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-hydroxy-cyclohexyl]acetate(150 mg, 0.50 mmol) was added to the above material, and the mixture wasco-evaporated with anhydrous toluene (2×10 mL) and then was dried underreduced pressure for 2 h. The material was dissolved in anhydrous Et₂O(5 mL) and then grounded activated 3 Å (0.5 g) and 4 Å sieves (0.5 g)were added. The mixture was stirred at room temperature for 1 h, thencooled to −40° C. TIVISOTf (0.027 mL, 0.15 mmol) was then added dropwiseand the mixture was stirred at −40° C. for 2 h, then warmed to roomtemperature. A saturated solution of NaHCO₃ (200 mL) was added and theseparated aqueous layer was extracted with EtOAc (3×200 mL). Thecombined organic layers were dried (MgSO₄), filtered and concentratedunder reduced pressure. The material was purified by flashchromatography (24 g, liquid loading) using a gradient of 0-40% EtOAc inhexane as eluent to afford intermediate A (minor, first eluting) andintermediate B (major, second eluting). MS (ESI) [M+Na]⁺731.5.

To a solution of intermediate B in MeOH (5 mL), NaOMe (4.62 M in MeOH,0.87 mL, 4.02 mmol) was added and the reaction mixture was stirred atroom temperature for 1 h. The mixture was concentrated under reducedpressure and the residue was dissolved in DCM (25 mL) and then asaturated solution of NH₄Cl (25 mL) was added. The separated aqueouslayer was extracted with DCM (2×20 mL). The combined organic layers weredried (MgSO₄), filtered and concentrated under reduced pressure toprovide the title compound (70.0 mg, 22%) MS (ESI) [M+Na]⁺647.5.

Step 8 BenzylN-[(1S)-1-[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]-2-fluoro-ethyl]-N-benzyl-carbamate

To a solution of benzylN-[(1S)-1-[(2S,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]-2-fluoro-ethyl]-N-benzyl-carbamate(88.0 mg, 0.14 mmol) in dry DCM (8 mL), was added pyridine (67 μL, 0.85mmol) followed by Ac₂O (67 μL, 0.70 mmol) at room temperature and thereaction mixture was stirred for 20 h. MeOH was added and the volatileswere evaporated under reduced pressure. The material was purified byflash chromatography (12 g, liquid loading with toluene) using agradient 0-45% EtOAc in hexane as eluent to provide the title compound(63 mg, 67%). MS (ESI) [M+H]⁺667.7.

Step 9Benzyl-N-[(1S)-1-[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2-[(2S,3R,4S,5R)-4-[(2R,3R,4R,5S,6S)-3-azido-6-(azidomethyl)-4,5-dihydroxy-tetrahydropyran-2-yl]oxy-3-hydroxy-5-thydroxymethyl)tetrahydrofuran-2-yl]oxy-3-hydroxy-cyclohexoxy]tetrahydropyran-2-yl]-2-fluoro-ethyl]-N-benzyl-carbamate

To a suspension of[(2R,3R,4R)-4-acetoxy-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-5-hydroxy-tetrahydrofuran-2-yl]methylacetate (150 mg, 0.28 mmol) and K₂CO₃ (78.4 mg, 0.57 mmol) in dry DCM(5.0 mL) at ambient temperature under N₂, was added CCl₃CN (0.095 mL,0.95 mmol) dropwise and the reaction mixture was stirred for 15 h. Themixture was filtered through 45 μm nylon filter and the volatiles wereevaporated under reduced pressure.

To the above material was added a solution of[(1S,2S,3R,4S,6R)-4,6-diazido-3-[(2R,3R,6S)-3-azido-6-[(1S)-1-[benzyl(benzyloxycarbonyl)amino]-2-fluoro-ethyl]tetrahydropyran-2-yl]oxy-2-hydroxy-cyclohexyl]acetate(63.0 mg, 0.095 mmol) in DCM (1.0 mL) and the volatiles were evaporatedunder reduced pressure. To the residue was added ground 4 A sieves (200mg) followed by dry DCM (5.0 mL). The suspension was stirred at ambienttemperature for 1 h. The solution was cooled to 0° C. and then BF₃Et₂O(0.093 mL, 0.76 mmol) was added. The reaction mixture was stirred for 2h, and then the reaction was quenched with NaHCO₃. The layers wereseparated, and the aqueous layer was extracted with EtOAc (5.0 mL). Theorganic phase was dried (Na₂SO₄), filtered and concentrated underreduced pressure. The material was purified by reversed phasechromatography on C18 (80 g) using ACN in water and 0.1% aqueous. formicacid (40-100%) to afford the title compound. MS (ESI) [M+Na]⁺1201.8.

To a solution of the above material in MeOH (1.0 mL) at ambienttemperature, was added NaOMe (25 wt %, 0.33 mL, 1.13 mmol) dropwise andthe reaction mixture was stirred for 45 min. The volatiles were removedunder reduced pressure. The residue was diluted with EtOAc and theorganic layer was washed with saturated NH₄Cl and brine, then dried(Na₂SO₄), filtered, and concentrated under reduced pressure. Thematerial was purified by preparative HPLC (CSH ACN/AmForm 60-80%) toafford the title compound (19 mg, 21%, 3 steps). MS (ESI) [M+H]⁺969.7.

Step 10(2S,3S,4R,5R,6R)-5-amino-2-(aminomethyl)-6-[(2R,3S,4R,5S)-5-[(1R,2R,3S,5R,6S)-3,5-diamino-2-[(2R,3R,6S)-3-amino-6-[(1S)-1-amino-2-fluoro-ethyl]tetrahydropyran-2-yl]oxy-6-hydroxy-cyclohexoxy]-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl]oxy-tetrahydropyran-3,4-diol,Sulfate

To a solution of benzylN-[(1S)-1-[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2-[(2S,3R,4S,5R)-4-[(2R,3R,4R,5S,65)-3-azido-6-(azidomethyl)-4,5-dihydroxy-tetrahydropyran-2-yl]oxy-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]oxy-3-hydroxy-cyclohexoxy]tetrahydropyran-2-yl]-2-fluoro-ethyl]-N-benzyl-carbamate(19 mg, 0.020 mmol) and Pd/C (10% dry on carbon, 10.4 mg, 0.0098 mmol)following by anhydrous MeOH (1 mL). Nitrogen was bubbled for 5 min, thenammonium formate (18.5 mg, 0.29 mmol) was added and the mixture washeated at 63° C. for 6 h. The mixture was then cooled and filteredthrough a nylon filter (45 pin) and the volatiles were evaporated underreduced pressure to provide the title compound (7.7 mg, 64%). Thematerial was purified by preparative HPLC (with A: 0.3% HFBA, 0.3% HCOOHin water B: 0.3% HFBA Acetonitrile; Flow rate: 40 mL/min; Column : C18,30×150 mm, 27% B in A to 37% B in A over 7 minutes provided 8 mg of thetitle compound as a HFBA salt. The salt swap with ammonium sulfateprovided the title product (0.7 mg, 6%). ¹1-INMR (500 MHz, D20) δ 5.86(d, J=3.5 Hz, 1H), 5.35 (d, J=2.3 Hz, 1H), 5.24 (d, J=1.7 Hz, 1H),4.83-4.74 (m, 1H), 4.68-4.63 (m, 1H), 4.47 (dd, J=6.7, 4.9 Hz, 1H), 4.38(dd, J=4.8, 2.3 Hz, 1H), 4.30-4.25 (m, 1H), 4.22-4.14 (m, 3H), 4.00 (s,1H), 3.88-3.82 (m, 2H), 3.79-3.64 (m, 4H), 3.56-3.52 (m, 1H), 3.52-3.46(m, 1H), 3.43-3.24 (m, 4H), 2.36 (dt, J=6.9, 4.6 Hz, 1H), 2.02-1.93 (m,2H), 1.93-1.83 (m, 2H), 1.70-1.58 (m, 1H). MS (ESI) [M+H]⁺615.0.

Example 24

Step 1 BenzylN-[[(2S,5R,6R)-6-[[(3aR,5S,6R,7S,7aS)-5-(benzyloxycarbonylamino)-7-hydroxy-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-1,3-benzoxazol-6-yl]oxy]-5-(benzyloxycarbonylamino)tetrahydropyran-2-yl]methyl]-N-benzyl-carbamate

To a solution of benzylN-[[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]methyl]-N-benzyl-carbamate(see Example 11 for synthesis, 335 mg, 565 μmol) and water (350 μL, 19.4mmol) in THF (12.0 mL) under N₂ at, was added PMe₃ (1.0 M in THF, 2.54mL, 2.54 mmol) ambient temperature. The reaction mixture was heated to40° C. and stirred for 18 h. The mixture was cooled to room temperatureand then K₂CO₃ (703 mg, 5.09 mmol) was added and stirred for 10 min.CbzCl (362 μL, 2.54 mmol) was added dropwise and the reaction mixturewas stirred for 60 min. Silica gel (5.0 g) was added and all volatileswere evaporated under reduced pressure. The material was purified bysilica gel chromatography (25 g cartridge, drypack) using a gradient ofMeOH and DCM (0-10%) as eluent to afford benzylN-benzyl-N-[[(2S,5R,6R)-5-(benzyloxycarbonylamino)-6-[(1R,2R,3S,4R,6S)-4,6-bis(benzyloxycarbonylamino)-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]methyl]carbamate(725 mg) as a solid.

A portion of benzylN-benzyl-N-[[(2S,5R,6R)-5-(benzyloxycarbonylamino)-6-[(1R,2R,3S,4R,6S)-4,6-bis(benzyloxycarbonylamino)-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]methyl]carbamate(200 mg) was dissolved in anhydrous DMF (0.80 mL) and then NaH (60%, 42mg, 1.05 mmol) was added under N₂ at 0° C. The flask was warmed toambient temperature and stirred for 40 min. The mixture was cooled to 0°C. and then acetic acid (69 μL, 1.20 mmol) was added dropwise. Thematerial was directly purified by silica gel chromatography (12 gcartridge) using a gradient of MeOH and DCM (0-10%) as eluent to affordthe title compound (120 mg, 95% over 3 steps) as a solid. MS (ESI)[M+H]⁺809.4.

Step 2[(2R,3R,4R,5S)-5-[[(3aR,5S,6R,7S,7aS)-6-[(2R,3R,6S)-6-[[benzyl(benzyloxycarbonyl)amino]methyl]-3-(benzyloxycarbonylamino)tetrahydropyran-2-yl]oxy-5-(benzyloxycarbonylamino)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-1,3-benzoxazol-7-yl]oxy]-4-acetoxy-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-tetrahydrofuran-2-yl]methylacetate

CCl₃CN (149 μL, 1.48 mmol) was added dropwise to a suspension of[(2R,3R,4R)-4-acetoxy-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-5-hydroxy-tetrahydrofuran-2-yl]methylacetate (157 mg, 297 μmol) and K₂CO₃ (123 mg, 890 μmol) in dry DCM (1.8mL) at ambient temperature under N₂. After 17 h, the solution wasfiltered through a Celite pad and the filtrate was concentrated under N₂stream, and then dried under high-vacuum. To the above material wasadded benzylN-[[(2S,5R,6R)-6-[[(3aR,5S,6R,7S,7aS)-5-(benzyloxycarbonylamino)-7-hydroxy-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-1,3-benzoxazol-6-yl]oxy]-5-(benzyloxycarbonylamino)tetrahydropyran-2-yl]methyl]-N-benzyl-carbamate(120 mg, 148 μmol) in DCM (1.8 mL) and all volatiles were evaporatedunder N₂ stream. To the mixture was added ground 4 Å sieves (450 mg) andthe mixture was dissolved in dry DCM (1.8 mL). The suspension wasstirred at ambient temperature for 90 min, and then cooled to 0° C.BF₃.OEt₂ (146 μL, 1.19 mmol) was added and then stirred at ambienttemperature for another 1 h. Et₃N (300 μL) was added and the mixture wasfiltered through a silica gel pad (0.30 g) and washed with EtOAc (20.0mL). The volatiles were evaporated under reduced pressure and thematerial was purified by silica gel chromatography (12 g cartridge)using a gradient of MeOH and DCM (0-5%) as eluent and was furtherpurified by C18 reversed phase chromatography (30 g cartridge) using ACNand 0.1% aq. formic acid (40-100%) to provide the title compound (83 mg,42%) as a solid. MS (ESI) [M+H]⁺1322.8.

Step 3 BenzylN-[[(2S,5R,6R)-6-[(1R,2R,3S,4R,6S)-4-amino-2-[(2S,3R,4S,5R)-4-[(2R,3R,4R,5S,6S)-3-azido-6-(azidomethyl)-4,5-dihydroxy-tetrahydropyran-2-yl]oxy-3-hydroxy-5-thydroxymethyl)tetrahydrofuran-2-yl]oxy-6-(benzyloxycarbonylamino)-3-hydroxy-cyclohexoxy]-5-(benzyloxycarbonylamino)tetrahydropyran-2-yl]methyl]-N-benzyl-carbamate

LiOH.H₂O (12 mg, 280 μmol) was added to a suspension of[(2R,3R,4R,5S)-5-[[(3aR,5S,6R,7S,7a5)-6-[(2R,3R,6S)-6-[[benzyl(benzyloxycarbonyl)amino]methyl]-3-(benzyloxycarbonylamino)tetrahydropyran-2-yl]oxy-5-(benzyloxycarbonylamino)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-1,3-benzoxazol-7-yl]oxy]-4-acetoxy-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-tetrahydrofuran-2-yl]methylacetate (37 mg, 28 μmol) in a mixture dioxane and water (2.0 mL, 1:1) atambient temperature. After 2 h, LiORH.H₂O (12 mg, 280 μmol) was addedand the reaction mixture was stirred for 18 h. All volatiles wereremoved under reduced pressure and the material was purified by silicagel chromatography (4 g cartridge) using a gradient of MeOH and DCM(0-20%) as eluent to provide the title compound (21 mg, 66%) as a solid.MS (ESI) [M+H]⁺1127.8.

Also from the same chromatography, benzylN-[[(2S,5R,6R)-6-[[(3aR,5S,6R,7S,7aS)-7-[(2S,3R,4S,5R)-4-[(2R,3R,4R,5S,6S)-3-azido-6-(azidomethyl)-4,5-dihydroxy-tetrahydropyran-2-yl]oxy-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]oxy-5-(benzyloxycarbonylamino)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-1,3-benzoxazol-6-yl]oxy]-5-(benzyloxycarbonylamino)tetrahydropyran-2-yl]methyl]-N-benzyl-carbamate(8 mg, 25%). MS (ESI) [M+H]⁺1154.6.

To a suspension of[(2R,3R,4R,5S)-5-[[(3aR,5S,6R,7S,7aS)-6-[(2R,3R,6S)-6-[[benzyl(benzyloxycarbonyl)amino]methyl]-3-(benzyloxycarbonylamino)tetrahydropyran-2-yl]oxy-5-(benzyloxycarbonylamino)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-1,3-benzoxazol-7-yl]oxy]-4-acetoxy-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-tetrahydrofuran-2-yl]methylacetate (45 mg, 34 μmol) and benzylN-[[(2S,5R,6R)-6-[[(3aR,5S,6R,7S,7aS)-7-[(2S,3R,4S,5R)-4-[(2R,3R,4R,5S,6S)-3-azido-6-(azidomethyl)-4,5-dihydroxy-tetrahydropyran-2-yl]oxy-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]oxy-5-(benzyloxycarbonylamino)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-1,3-benzoxazol-6-yl]oxy]-5-(benzyloxycarbonylamino)tetrahydropyran-2-yl]methyl]-N-benzyl-carbamate(8 mg, 7 μmol) in a mixture dioxane and water (1:1; 2.0 mL) at ambienttemperature was added LiOH.H₂O (43 mg, 1.02 mmol) and the reactionmixture was stirred for 18 h.

All volatiles were evaporated under reduced pressure and the materialwas purified by silica gel chromatography (12 g cartridge) using agradient of MeOH and DCM (0-20%) as eluent to provide the title compound(34 mg, 74%) as a solid. MS (ESI) [M+H]⁺1127.8.

Overall, the hydrolysis of[(2R,3R,4R,5S)-5-[[(3aR,5S,6R,7S,7aS)-6-[(2R,3R,6S)-6-[[benzyl(benzyloxycarbonyl)amino]methyl]-3-(amino)tetrahydropyran-2-yl]oxy-5-(benzyloxycarbonylamino)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-1,3-benzoxazol-7-yl]oxy]-4-acetoxy-3-[(2R,3R,4R,5R,6S)-4,5-diacetoxy-3-azido-6-(azidomethyl)tetrahydropyran-2-yl]oxy-tetrahydrofuran-2-yl]methylacetate (82 mg, 62 μmol) afforded the title compound (55 mg) with 78%yield.

Step 4 BenzylN-[[(2S,5R,6R)-6-[(1R,2R,3S,4R,6S)-2-[(2S,3R,4S,5R)-4-[(2R,3R,4R,5S,6S)-3-azido-6-(azidomethyl)-4,5-dihydroxy-tetrahydropyran-2-yl]oxy-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]oxy-4-[[(2R,3R)-4-azido-2-benzyloxy-3-fluoro-butanoyl]amino]-6-(benzyloxycarbonylamino)-3-hydroxy-cyclohexoxy]-5-(benzyloxycarbonylamino)tetrahydropyran-2-yl]methyl]-N-benzyl-carbamate

PyBOP (30 mg, 59 μmol) was added to a solution of benzylN-[[(2S,5R,6R)-6-[(1R,2R,3S,4R,6S)-4-amino-2-[(2S,3R,4S,5R)-4-[(2R,3R,4R,5S,6S)-3-azido-6-(azidomethyl)-4,5-dihydroxy-tetrahydropyran-2-yl]oxy-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]oxy-6-(benzyloxycarbonylamino)-3-hydroxy-cyclohexoxy]-5-(benzyloxycarbonylamino)tetrahydropyran-2-yl]methyl]-N-benzyl-carbamate(55 mg, 49 μmol), (2R,3R)-4-azido-2-benzyloxy-3-fluoro-butanoic acid (14mg, 56 μmol) and DIPEA (20 μL, 146 μmol) in dry DMF (0.40 mL) under N₂and the reaction mixture was stirred for 60 min. The mixture wasdirectly purified by C18 reverse phase chromatography (12 g cartridge)using ACN and 0.1% aq formic acid (30-100%) as eluent to provide thetitle compound (40 mg, 60%) as a solid. MS (ESI) [M+H]⁺1363.9.

Step 5(2R,3R)-4-amino-N-[(1R,2S,3R,4R,5S)-5-amino-3-[(2S,3R,4S,5R)-4-[(2R,3R,4R,5S,6S)-3-amino-6-(aminomethyl)-4,5-dihydroxy-tetrahydropyran-2-yl]oxy-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]oxy-4-[(2R,3R,6S)-3-amino-6-(aminomethyl)tetrahydropyran-2-yl]oxy-2-hydroxy-cyclohexyl]-3-fluoro-2-hydroxy-butanamide;2,2,3,3,4,4,4-heptafluorobutanoicacid

Pd(OH)₂/C (10 wt %, 82 mg, 59 μmol) was added to a solution of benzylN-[[(2S,5R,6R)-6-[(1R,2R,3S,4R,6S)-2-[(2S,3R,4S,5R)-4-[(2R,3R,4R,5S,6S)-3-azido-6-(azidomethyl)-4,5-dihydroxy-tetrahydropyran-2-yl]oxy-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]oxy-4-[[(2R,3R)-4-azido-2-benzyloxy-3-fluoro-butanoyl]amino]-6-(benzyloxycarbonylamino)-3-hydroxy-cyclohexoxy]-5-(benzyloxycarbonylamino)tetrahydropyran-2-yl]methyl]-N-benzyl-carbamate(21 mg, 27 μmol) in a mixture 4:1 AcOH/H₂O (2.0 mL) under N₂ at ambienttemperature. H₂ was bubbled into the solution for 15 min and thesuspension was hydrogenated under hydrogen atmosphere for 18 h. Thematerial was filtered through a frit (0.45 μm diameter) and concentratedunder reduced pressure. The material was purified by preparative HPLC(BEH 30×100 mm ACN/AmForm 10-15%) and was further purified byHFBA-coupled preparative HPLC (HFBA 25-40%) to provide the titlecompound (hexa-HFBA salt, 17.5 mg, 30%) as a solid. ¹H NMR (500 MHz,D₂O) δ 5.91 (d, J=3.3 Hz, 1H), 5.42 (d, J=1.8 Hz, 1H), 5.37-5.21 (m,2H), 4.52-4.41 (m, 2H), 4.38 (dd, J=4.5, 2.1 Hz, 1H), 4.33 (t, J=4.4 Hz,1H), 4.27-4.21 (m, 2H), 4.17-4.10 (m, 1H), 4.08-3.97 (m, 2H), 3.95 (dd,J=12.3, 2.5 Hz, 1H), 3.90 (t, J=9.1 Hz, 1H), 3.86 (s, 1H), 3.76 (dd,J=12.2, 5.4 Hz, 1H), 3.67 (t, J=9.8 Hz, 1H), 3.61 (s, 1H), 3.59-3.53 (m,2H), 3.53-3.37 (m, 4H), 3.27 (dd, J=13.5, 3.1 Hz, 1H), 3.12 (dd, J=13.5,7.0 Hz, 1H), 2.34-22.26 (m, 1H), 2.11 2.01 (m, 2H), 1.99-1.91 (m, 1H),1.89-1.78 (m, 1H), 1.68-1.56 (m, 1H). MS (ESI) [M+H]⁺702.4.

Example 25(1S,2R,3R,4S,6R)-4,6-diamino-3-(((2R,3R,6S)-3-amino-6-((S)-1-aminoethyl)tetrahydro-2H-pyran-2-yl)oxy)cyclohexane-1,2-diol

Pd(OH)₂/C (20 wt %, 145 mg, 206 μmol) was added to a solution of benzylN-[(1S)-1-[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxycyclohexoxy]tetrahydropyran-2-yl]ethyl]-N-benzyl-carbamate(see Example 2 for synthesis, 25.0 mg, 41.2 μmol) in MeOH (2.50 mL) andEtOH (2.50 mL). H₂ was bubbled and the suspension was hydrogenated underhydrogen atmosphere for 16 h. The mixture was filtered through a frit(0.22 μm diameter) and the filtrate was concentrated under reducedpressure to afford the title compound (11.0 mg, 88%) as a solid. ¹H NMR(500 MHz, MeOD) δ 5.47 (d, J=3.5 Hz, 1H), 3.75-3.68 (m, 1H), 3.43 (t,J=9.1 Hz, 1H), 3.37-3.31 (m, 1H), 3.12 (t, J=9.5 Hz, 1H), 3.07-3.00 (m,1H), 2.95-2.86 (m, 2H), 2.79-2.72 (m,1H), 2.06-2.00 (m, 1H), 1.87-1.73(m, 3H), 1.46-1.36 (m, 1H), 1.28-1.14 (m, 4H). MS (ESI) [M+H]⁺305.0.

Example 26

Step 1[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-[(6S)-6-[(1R)-1-(benzyloxycarbonylamino)ethyl]tetrahydropyran-2-yl]oxy-cyclohexyl]acetate

CSA (97.8 mg, 0.42 mmol) was added to a solution of benzylN-[(1R)-1-[(2S)-3,4-dihydro-2H-pyran-2-yl]ethyl]carbamate (see Example27, 100 mg, 0.38 mmol) andDL-[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-hydroxy-cyclohexyl]acetate(126 mg, 0.42 mmol) in toluene (5 mL) at room temperature. The mixturewas stirred at room temperature for 5 h, then a saturated aqueoussolution of NaHCO₃ (5 mL) was added. The aqueous layer was extractedwith DCM. The combined organic layer was driver over MgSO₄ andconcentrated under reduced pressure. The material was purified by prepHPLC (ACN, AmFor, BEH column) to provide the title compound (103 mg)with 48% as a solid. 1H NMR (500 MHz, CDCl₃) δ 7.33 7.23 (m, 5H),5.08-5.02 (m, 2H), 4.96-4.88 (m, 3H), 4.53 (dd, J=9.5, 1.8 Hz, 1H),3.74-3.63 (m, 1H), 3.58-3.50 (m, 1H), 3.50-3.42 (m, 2H), 3.26 (dd,J=11.0, 4.5 Hz, 1H), 2.20 (dt, J=13.4, 4.5 Hz, 1H), 2.01 (s, 3H), 1.95(s, 3H), 1.84-1.74 (m, 2H), 1.45-1.34 (m, 3H), 1.27-1.17 (m, 2H), 1.13(d, J=6.7 Hz, 3H).

Step 2 BenzylN-[(1R)-1-[(2S,6R)-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]ethyl]carbamate

A MeONa solution (0.50 M, 1.47 mL, 736 μmol) in MeOH was added dropwiseto a solution of[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-[(2R,6S)-6-[(1R)-1-(benzyloxycarbonylamino)ethyl]tetrahydropyran-2-yl]oxy-cyclohexyl]acetate(103 mg, 184 μmol) in methanol (4.6 mL). After 1 h, AcOH (63 μL, 1.10mmol) was added to the solution. All volatiles were evaporated, and thecrude was purified by silica gel chromatography (4 g cartridge) withEtOAc and hexanes (10-50%) to provide the title compound, which wasfurther purified by prep-HPLC to produce the title compound as a solid(29 mg, 32%). ¹H NMR (500 MHz, DMSO) δ 7.40-7.26 (m, 5H), 7.11 (d, J=8.9Hz, 1H), 5.51 (t, J=4.4 Hz, 2H), 5.29 (d, J=5.6 Hz, 1H), 5.01 (d, J=12.5Hz, 1H), 4.97 (d, J=12.5 Hz, 1H), 3.81-3.73 (m, 1H), 3.56-3.44 (m, 2H),3.44-3.34 (m, 2H), 3.27-3.20 (m, 1H), 3.14 (td, J=9.4, 5.5 Hz, 1H), 2.03(dt, J=12.5, 4.4 Hz, 1H), 1.76-1.61 (m, 2H), 1.52 (ddd, J=18.9, 16.5,8.5 Hz, 3H), 1.18 (dd, J=24.8, 12.4 Hz, 2H), 1.06 (d, J=6.8 Hz, 3H).LCMS m/z: ES⁺[M+H]⁺: 476.24; (A05) retention time=2.35 m.

Step 3(1S,2R,3R,4S,6R)-4,6-diamino-3-[(2R,6S)-6-[(1R)-1-aminoethyl]tetrahydropyran-2-yl]oxy-cyclohexane-1,2-diol

A solution of benzylN-[(1R)-1-[(2S,6R)-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]ethyl]carbamate(8.5 mg, 0.02 mmol) and 20% wt Pd(OH)₂ (2.5 mg, 0.004 mmol) in MeOH/EtOH(5 mL, 1:1) was hydrogenated at room temperature for 18 hours. Themixture was degassed with N₂ and filtered on celite. The mixture wasconcentrated under reduced pressure to provide the title compound (4.66mg, 90%) as a solid. M+Na+: 312.1. ¹H NMR (500 MHz, MeOD) δ 5.50 (d,J=3.0 Hz, 1H), 3.94-3.89 (m, 1H), 3.26-3.19 (m, 2H), 3.12-3.06 (m, 1H),3.02-2.97 (m, 1H), 2.80-2.73 (m, 1H), 2.62 (ddd, J=12.0, 9.7, 4.2 Hz,1H), 1.94 (dt, J=12.8, 4.2 Hz, 1H), 1.85-1.78 (m, 2H), 1.65-1.53 (m,3H), 1.35 (qd, J=12.2, 3.7 Hz, 1H), 1.23-1.18 (m, 1H), 1.15 (d, J=5.2Hz, 3H).

Example 27

Step 1 Benzyl N-[(1R)-1-[(2S)-3,4-dihydro-2H-pyran-2-yl]ethyl]carbamate

HCl (4 M, 842 μL, 3.37 mmol) was added dropwise into a solution ofN-[(1R)-1-[(2S)-3,4-dihydro-2H-pyran-2-yl]ethyl]-2-methyl-propane-2-sulfinamide(780 mg, 3.37 mmol) and isopropanol (309 μL, 4.05 mmol) in EtOAc (7.0mL) at ambient temperature. After 90 min, triethylamine (600 μL, 4.30mmol) was added and all volatiles were removed under reduced pressure.The crude was dissolved in THF (12.0 mL) and water (3.0 mL) followed bythe addition of K₂CO₃ (932 mg, 6.74 mmol). After 15 min, CbzCl (575 μL,4.05 mmol) was dropwise added to the solution. After another 2 h, THFwas evaporated and the remainder was partitioned in between EtOAc (20.0mL) and water (20.0 mL). The organic layer was washed with brine (10.0mL), dried (Na₂SO₄), filtered and concentrated under reduced pressure.The crude was purified by silica gel chromatography (25 g cartridge)with EtOAc and hexanes (5%-20%) to provide the title compound as a solid(125 mg, 13%). LCMS m/z: ES⁺[M+H]⁺: 262.16; (A05) retention time=2.44 m.

Step 2[(6S)-3-azido-6-[(1R)-1-(benzyloxycarbonylamino)ethyl]tetrahydropyran-2-yl]acetate

A solution of benzylN-[(1R)-1-[(2S)-3,4-dihydro-2H-pyran-2-yl]ethyl]carbamate (112 mg, 429μmol) in dry MeCN (1.0 mL) was added to solid CAN (0.705 g, 1.29 mmol)and NaN₃ (56 mg, 857 μmol) at −20° C. dropwise under N₂. After theaddition, dry MeCN (0.50+0.50 mL) was used to transfer all material. Thesolution was kept within −25˜−15° C. for 7 h. The solution was dilutedwith water (20.0 mL) and Et₂O (20.0 mL) and the organic layer wassuccessively washed with water (10.0 mL) and brine (5.0 mL), dried(Na₂SO₄), filtered and concentrated under reduced pressure. The crudewas dissolved in HOAc (2.0 mL) and was added NaOAc (11 mg, 129 μmol).After 20 h, all solvents were removed under reduced pressure and thecrude was purified by silica gel chromatography (4 g cartridge) withEtOAc and hexanes (10-40%) to produce the title compound (mixture ofdiastereomers) as an oil (79 mg, 48%). LCMS m/z: ES+ [M+H]⁺: 363.04,[M-OAc]⁺: 303.27; (A05) retention time=2.40 and 2.44 m.

Step 3[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-[(2R,3S,6S)-3-azido-6-[(1R)-1-(benzyloxycarbonylamino)ethyl]tetrahydropyran-2-yl]oxy-cyclohexyl]acetate

Dry DCM (2.0 mL) was added into a solid mixture of[(6S)-3-azido-6-[(1R)-1-(benzyloxycarbonylamino)ethyl]tetrahydropyran-2-yl]acetate(75 mg, 207 μmol),[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-hydroxy-cyclohexyl]acetate (80mg, 268 μmol) and pulverized 4 Å molecular sieves (600 mg) under N₂.After 1 h, the solution was cooled to 0° C. and BF₃.OEt₂ (89 μL, 717μmol) was added dropwise with rapid stirring. After 1 h, the solutionwas warmed to room temperature. After another 22 h, another portion ofBF₃.OEt₂ (89 μL, 717 μmol) was added dropwise with rapid stirring. Afteranother 6 h, sat, NaHCO₃ (5.0 mL) was added to the reaction mixture. Themixture was extracted by EtOAc (10.0 mL) and the organic layer wassuccessively washed with water (5.0 mL) and brine (5.0 mL). The crudewas purified by silica gel chromatography (12 g cartridge) with EtOAcand hexanes (5-30%) to provide the title compound as a solid (12 mg,10%). LCMS m/z: ES⁺[M+14]⁺: 601.28, M-DOW: 303.24; (A05) retentiontime=2.69 m.

Step 4 BenzylN-[(1R)-1-[(2S,5S,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]ethyl]carbamate

A MeONa solution (25 wt %, 23 μL, 100 μmol) in MeOH was added dropwiseto a solution of[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-[(2R,6S)-6-[(1R)-1-(benzyloxycarbonylamino)ethyl]tetrahydropyran-2-yl]oxy-cyclohexyl]acetate(12 mg) in methanol (1.0 mL). After 1 h, HOAc (30 μL, 525 mmol) wasadded to the solution. All volatiles were evaporated and the crude waspurified by silica gel chromatography (4 g cartridge) with EtOAc andhexanes (20-50%) to provide the title compound as a film (7 mg, 66%). ¹HNMR (500 MHz, MeOD) δ 7.45-7.22 (m, 5H), 5.50 (s, 1H), 5.16-5.04 (m,2H), 4.16-4.03 (m, 1H), 3.75-3.66 (m, 1H), 3.64 (s, 1H), 3.55-3.45 (m,2H), 3.43-3.35 (m, 2H), 3.23 (t, J=9.5 Hz, 1H), 2.22-2.08 (m, 2H), 1.85(dd, J=14.0, 2.6 Hz, 1H), 1.66 (qd, J=13.2, 3.7 Hz, 1H), 1.46 (d, J=13.7Hz, 1H), 1.24 (dt, J=12.8, 9.4 Hz, 1H), 1.19 (d, J=6.9 Hz, 3H). LCMSm/z: ES⁺[M+H]⁺: 517.25; (A05) retention time=2.39

Step 5(1S,2R,3R,4S,6R)-4,6-diamino-3-[(2R,3S,6S)-3-amino-6-[(1R)-1-aminoethyl]tetrahydropyran-2-yl]oxy-cyclohexane-1,2-diol

Pd(OH)₂/C (10 wt %, 4.5 mg, 3.3 μmol) was added to a solution of benzylN-[(1R)-1-[(2S,5S,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]ethyl]carbamate(7 mg, 13.6 μmol) in EtOH/MeOH (1:1, 3.0 mL) under N₂ at ambienttemperature. H₂ was bubbled through the suspension for 10 min. After 17h, the solution was filtered through a frit (0.22 μm diameter) and thefiltrate was concentrated under reduced pressure, then lyophilized toprovide the title compound as a solid (4.7 mg, 114%). ¹H NMR (500 MHz,MeOD) δ 5.06 (d, J=1.9 Hz, 1H), 3.87-3.79 (m, 1H), 3.30 (t, J=9.1 Hz,1H), 3.23 (t, J=9.2 Hz, 1H), 3.05 (t, J=9.4 Hz, 1H), 3.02-2.98 (m, 1H),2.96 (dd, J=6.2, 3.8 Hz, 1H), 2.76 (ddd, J=12.2, 9.4, 4.2 Hz, 1H), 2.64(ddd, J=12.0, 9.6, 4.1 Hz, 1H), 2.12-2.04 (m, 1H), 2.01 (dt, J=12.9, 4.2Hz, 1H), 1.75-1.62 (m, 2H), 1.51-1.44 (m, 1H), 1.28-1.22 (m, 1H), 1.15(d, J=6.7 Hz, 3H). LCMS m/z: [M+H]⁺: 305.19; [M+Na]+: 327.14.

Example 28

Step 1[(6S)-2-acetoxy-6-[(1R)-1-(benzyloxycarbonylamino)ethyl]tetrahydropyran-3-yl]acetate

OsO₄ (4.0 mg, 0.02 mmol) was added to a solution of benzylN-[(1R)-1-[(2S)-3,4-dihydro-2H-pyran-2-yl]ethyl]carbamate (210 mg, 0.80mmol) and NMO (235 mg, 2.01 mmol) in acetone (10 mL). The mixture wasstirred at room temperature for 18 h, then filtered on Florisil, rinsedwith EtOAc and concentrated under reduced pressure. The residue wastaken in dry pyridine (10 mL) and acetic anhydride (0.30 mL, 3.21 mmol)was added. The mixture was stirred at room temperature for 18 h, thenwater (50 mL) was added. The separated aqueous layer was extracted withDCM. The combined organic was washed with brine, dried over MgSO₄ andconcentrated under reduced pressure. The material was purified on silicagel (40 g, dry loading) by MPLC using 0% to 50% EtOAc in hexane toprovide the title compound (280 mg, 92%) as a mixture of 3diastereoisomers.

Step 2[(6S)-6-[(1R)-1-(benzyloxycarbonylamino)ethyl]-2-[(1R,2S,3S,4R,6S)-2,3-diacetoxy-4,6-diazido-cyclohexoxy]tetrahydropyran-3-yl]acetate

BF₃.OEt₂ (0.09 mL, 0.7 mL) was added to a mixture of[rac-(6S)-2-acetoxy-6-[rac-(1R)-1-(benzyloxycarbonylamino)ethyl]tetrahydropyran-3-yl]acetate(180 mg, 0.474 mmol) and[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-hydroxy-cyclohexyl]acetate(283 mg, 0.95 mmol) in DCM (50 mL) at −78° C. The acetone/dry ice bathwas removed, and the mixture was stirred 6 h at room temperature. Asaturated aqueous solution of NaHCO₃ (50 mL) was added. The aqueouslayer was extracted with DCM. The combined organic layers were driedover Na₂SO₄ and concentrated under reduced pressure. The product waspurified by prep HPLC and provided a mixture of 3 diastereoisomers. 195mg (2 dia) −32% yield.

Step 3 BenzylN-[(1R)-1-[(2S,5R,6R)-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]-5-hydroxy-tetrahydropyran-2-yl]ethyl]carbamate

Sodium methoxide (4.62 M in methanol, 0.17 mL, 0.77 mmol) was added to asolution of[(6S)-6-[(1R)-1-(benzyloxycarbonylamino)ethyl]-2-[(1R,25,3S,4R,6S)-2,3-diacetoxy-4,6-diazido-cyclohexoxy]tetrahydropyran-3-yl]acetate(95 mg, 0.157 mmol) in dry MeOH (6.0 mL). The mixture was stirred atroom temperature for 4 h, then AcOH (0.05 mL, 0.923 mmol) was added. Themixture was concentrated under reduced pressure. The material waspurified by prep-HPLC to provide the desired compound (major anomer: 37mg, 48%) ¹H NMR (500 MHz, MeOD) δ 7.44-7.23 (m, 5H), 5.28 (d, J=3.1 Hz,1H), 4.01-3.87 (m, 1H), 3.70-3.56 (m, 2H), 3.52-3.43 (m, 2H), 3.43-3.34(m, 2H), 3.30-3.24 (m, 1H), 2.24-2.13 (m, 1H), 1.89-1.80 (m, 1H),1.80-1.72 (m, 1H), 1.69 (d, J=12.8 Hz, 1H), 1.50-1.36 (m, 1H), 1.36-1.26(m, 1H), 1.14 (d, J=6.7 Hz, 3H).

Step 4(1S,2R,3R,4S,6R)-4,6-diamino-3-[(2R,3R,6S)-6-[(1R)-1-aminoethyl]-3-hydroxy-tetrahydropyran-2-yl]oxy-cyclohexane-1,2-diol

A mixture of benzylN-[(1R)-1-[(2S,5R,6R)-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]-5-hydroxy-tetrahydropyran-2-yl]ethyl]carbamate(12 mg, 0.024 mmol) and Pd(OH)₂ (20% on dry support, 3.5 mg, 0.005 mmol)in MeOH/EtOH (5 mL, 1:1) was hydrogenated at room temperature for 18 h.The mixture was filtered with a 0.45 μM filter syringe and the solventwas removed under reduced pressure to provide the title compound (5.66mg, 76%) as a solid. M+Na⁺: 329.7 ¹H NMR (500 MHz, D₂O) δ 5.31 (d, J=3.5Hz, 1H), 4.03-3.97 (m, 1H), 3.85-3.77 (m, 1H), 3.55 (t, J=9.3 Hz, 1H),3.40-3.32 (m, 2H), 3.26 (t, J=9.6 Hz, 1H), 2.96 (ddd, J=12.1, 9.7, 4.3Hz, 1H), 2.86 (ddd, J=12.1, 9.9, 4.2 Hz, 1H), 2.07 (dt, J=12.9, 4.2 Hz,1H), 1.92-1.88 (m, 1H), 1.87-1.78 (m, 2H), 1.58-1.47 (m, 1H), 1.35-1.27(m, 1H), 1.23 (d, J=6.8 Hz, 3H).

Example 29 Step 1 Benzyl((R)-1-(2S,5S,6R)-6-(((1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxycyclohexyl)oxy)-5-hydroxytetrahydro-2H-pyran-2-yl)ethyl)carbamate

Sodium methoxide (4.62 M in methanol, 0.05 mL, 0.22 mmol) was added to asolution of[(6S)-6-[(1R)-1-(benzyloxycarbonylamino)ethyl]-2-[(1R,2S,3S,4R,6S)-2,3-diacetoxy-4,6-diazido-cyclohexoxy]tetrahydropyran-3-yl]acetate(as made in Example 28, 23 mg, 0.037 mmol) in dry MeOH (6.0 mL). Themixture was stirred at room temperature for 4 h, then AcOH (0.02 mL,0.261 mmol) was added. The mixture was concentrated under reducedpressure. The material was purified by prep-HPLC to provide the titlecompound (11 mg, 59%) as a solid. M+H⁺492.34.

Step 2(1S,2R,3R,4S,6R)-4,6-diamino-3-[(2R,3S,6S)-6-[(1R)-1-aminoethyl]-3-hydroxy-tetrahydropyran-2-yl]oxy-cyclohexane-1,2-diol

A mixture of benzylN-[(1R)-1-[(2S,5S,6R)-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]-5-hydroxy-tetrahydropyran-2-yl]ethyl]carbamate(8 mg, 0.016 mmol) and Pd(OH)₂ (20% on dry support, 2.3 mg, 0.003 mmol)in MeOH/EtOH (5 mL, 1:1) was hydrogenated at room temperature for 18 h.The mixture was filtered with a 0.45 uM filter syringe and the solventwas removed under reduced pressure to provide the title compound (3.64mg, 73%) as a solid. M+H⁺: 306.2. ¹H NMR (500 MHz, D₂O) δ 5.19 (s, 1H),4.05 (dt, J=12.0, 2.9 Hz, 1H), 3.86-3.80 (m, 1H), 3.49-3.37 (m, 4H),3.18-3.10 (m, 1H), 3.10 3.01 (m, 1H), 2.21 (dt, J=12.5, 4.0 Hz, 1H),1.99 1.90 (m, 1H), 1.81 1.75 (m, 1H), 1.69 1.43 (m, 3H), 1.22 (d, J=6.9Hz, 3H).

Example 30

Step 1 3,4-Dihydro-2H-pyran-2-ylmethyl acetate

Ac₂O (10.0 mL, 106 mmol) was added to a solution of3,4-dihydro-2H-pyran-2-ylmethanol (5.00 g, 43.8 mmol) in dry pyridine(20.0 mL). After 30 min, most of volatiles were removed under reducedpressure, then MeOH (10.0 mL) was added. All volatiles were removedunder reduced pressure to yield the title compound as a liquid (7.80 g,93%). This material was used in the next steps without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ 6.35 (d, J=5.9 Hz, 1H),4.76-4.63 (m, 1H), 4.21-4.08 (m, 2H), 4.08-3.98 (m, 1H), 2.10-1.93 (m,7H), 1.88-1.77 (m, 1H), 1.73-1.60 (m, 1H).

Step 2 [(2S)-3,4-dihydro-2H-pyran-2-yl]methanol

A solution of DL-3,4-dihydro-2H-pyran-2-ylmethyl acetate (3.20 g, 19.5mmol) in acetone (10.0 mL) was added to a pH 7.4 phosphate buffer (0.010M, 1.10 L, containing 343 mg NaH₂PO₄H₂O and 1210 mg Na₂HPO₄) withvigorous stirring in an Erlenmeyer flask. More acetone (3×9.0 mL) wasused to quantitatively transfer all material. PPL-II (300 mg) was addedto the reaction mixture and the solution was stirred at ambienttemperature (20° C.) for 16 h. The reaction mixture was thensuccessively extracted with EtOAc (200+100+100+100 mL). The combinedorganic layers were dried (Na₂SO₄), filtered and concentrated underreduced pressure. The crude was purified by silica gel chromatography(80 g cartridge) with EtOAc and hexanes (40-50%) to provide the titlecompound as a volatile oil (540 mg, 72%). This material was used in thenext step without further purification.

Step 3 Benzyl N-[[(2S)-3,4-dihydro-2H-pyran-2-yl]methyl]carbamate

DEAD (922 μL, 5.68 mmol) was added to a solution of[(2S)-3,4-dihydro-2H-pyran-2-yl]methanol (540 mg, 4.73 mmol) and PPh₃(1.49 g, 5.68 mmol) in dry THF (19.0 mL) dropwise at 0° C. under N₂.Then DPPA (1.22 mL, 5.68 mmol) was added to the reaction mixturedropwise. The solution was warmed to ambient temperature and stirred for16 h. PPh₃ (1.49 g, 5.68 mmol) was added to the reaction mixture(CAUTION: gas evolution). After 30 min, deionized water (1.6 mL, 90.0mmol) was added to the solution and the reaction was warmed to 50° C.under a refluxing condenser. After another 4 h, the solution was cooledto room temperature and K₂CO₃ (1.31 g, 9.46 mmol) was added. Afteranother 30 min, CbzCl (0.81 mL, 5.68 mmol) was added dropwise. Afteranother 60 min, THF was evaporated under reduced pressure and theresidue was diluted with sat. NaHCO₃ (20.0 mL), successively extractedwith ether (30.0+20.0+20.0 mL). The combined organic layer was dried(Na₂SO₄), filtered and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (25 g cartridge) with EtOAcand hexanes (5-20%) to produce the title compound as a solid (860 mg,73%). LCMS m/z: ES+[M+H]+: 248.33; (A05) retention time=2.37 m.

Step 4(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-[(2R,65)-6-(benzyloxycarbonylaminomethyl)tetrahydropyran-2-yl)oxy-cyclohexyl]acetate

CSA (207 mg, 0.89 mmol) was added to a solution of benzylN-[[(2S)-3,4-dihydro-2H-pyran-2-yl]methyl]carbamate (200 mg, 0.81 mmol)andDL-[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-hydroxy-cyclohexyl]acetate(265 mg, 0.89 mmol) in toluene (15 mL) at room temperature. The mixturewas stirred at room temperature for 4 h, then a saturated aqueoussolution of NaHCO₃ (10 mL) was added. The aqueous layer was extractedwith DCM. The combined organic layer was dried over MgSO₄ andconcentrated under reduced pressure. The crude was purified was purifiedby prep HPLC (ACN, AmFor, BEH column) to provide the title compound(along with some water left).

Step 5 BenzylN-[[(2S,6R)-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]methyl]carbamate

Sodium methoxide (4.62 M in methanol, 0.86 mL, 4.04 mmol) was added to asolution of[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-[(2R,6S)-6-(benzyloxycarbonylaminomethyl)tetrahydropyran-2-yl]oxy-cyclohexyl]acetate(441 mg, 0.81 mmol) in dry methanol (10.0 mL). After 1 h, HOAc (1.21 mL,21.2 mmol) was added to the solution. All volatiles were evaporated, andthe crude was purified by quick silica gel chromatography (4 gcartridge) with EtOAc and hexanes (20-70%) to give the product withslight impurity (60 mg) followed by prep HPLC (ACN, AmFor, BEH column)to give the title product (30 mg, 8% over two steps). LCMS m/z:ES⁺[M+H]⁺: 462.16; ES⁺[M-2DOS+H]⁺: 248.16. (A05) retention time=2.3 min.¹H NMR (500 MHz, MeOD) δ 7.30-7.11 (m, 5H), 5.41 (s, 1H), 4.97 (s, 2H),4.00 (dd, J=14.2, 7.1 Hz, 1H), 3.39-3.05 (m, 7H), 2.92 (dd, J=13.8, 7.7Hz, 1H), 2.03 (ddd, J=8.2, 6.8, 3.6 Hz, 1H), 1.89 (s, 2H), 1.84-1.71 (m,1H), 1.71-1.60 (m, 1H), 1.53-1.43 (m, 3H), 1.22-1.08 (m, 3H).

Step 6(1S,2R,3R,4S,6R)-4,6-diamino-3-[(2R,6S)-6-(aminomethyl)tetrahydropyran-2-yl]oxy-cyclohexane-1,2-diol

Pd(OH)₂/C (10 wt %, 7.6 mg, 5.4 μmol) was added to a flask containingbenzyl benzylN-[[(2S,6R)-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]methyl]carbamate(10 mg, 21.7 μmol) under N₂ at ambient temperature. EtOH/MeOH (1:1, 2.0mL) was added after which H₂ was bubbled through the suspension for 10min. After 17 h under hydrogen atmosphere (1 atm, balloon), the solutionwas filtered through a frit (0.45 μm diameter), rinsed with MeOH and thefiltrate was concentrated under reduced pressure, then lyophilized toprovide the title product (6.9 mg). ¹H NMR (500 MHz, D₂O) δ 5.41 (s,1H), 4.05-3.96 (m, 1H), 3.36-3.30 (m, 2H), 3.15-3.08 (m, 1H), 2.93 (dd,J=13.3, 3.6 Hz, 1H), 2.87 2.76 (m, 2H), 2.76-2.67 (m, 1H), 1.95 (dt,J=13.0, 4.2 Hz, 1H), 1.78-1.59 (m, 5H), 1.35-1.25 (m, 1H), 1.25-1.15 (m,1H).

Example 31

Step 1(R)—N—[(R)-[(2S)-3,4-dihydro-2H-pyran-2-yl]-phenyl-methyl]-2-methyl-propane-2-sulfinamide

PhLi (1.9 M in dibutyl ether, 12.2 mL, 23.22 mmol) was added to asolution of(NE,R)—N-[[(2S)-3,4-dihydro-2H-pyran-2-yl]methylene]-2-methyl-propane-2-sulfinamide(2.50 g, 11.61 mmol) in dry Toluene (100 mL) at −78° C. under N₂. After3 h, the reaction was warmed to −30° C. The reaction was quenched withadding sat. NH₄Cl dropwise dropwise (CAUTION: gas evolution). Two phaseswere separated, and the aqueous phase was extracted with DCM. Thecombined organic layers were dried (Na₂SO₄), filtered and concentratedunder reduced pressure. Purified by flash chromatography (80 gcartridge, 20-50% EtOAc in hexanes as eluent) to give the title product(3.55 g total, 87% based on both reactions). LCMS m/z: ES⁺[M+H]⁺: 294.09(A05) retention time=2.41 min.

¹H NMR (400 MHz, cdcl3) δ 7.41-7.24 (m, 5H), 6.35 (d, J=5.8 Hz, 1H),4.73-4.56 (m, 2H), 4.14-3.96 (m, 3H), 2.00-1.83 (m, 2H), 1.76-1.67 (m,1H), 1.52-1.40 (m, 1H), 1.20 (s, 9H).

Step 2(R)—N-benzyl-N—[(R)-[(2S)-3,4-dihydro-2H-pyran-2-yl]-phenyl-methyl]-2-methyl-propane-2-sulfinamide

NaH (60%, 367 mg, 9.19 mmol) was added to a mixture of(R)—N—[(R)-[(2S)-3,4-dihydro-2H-pyran-2-yl]-phenyl-methyl]-2-methyl-propane-2-sulfinamide(2.45 g, 8.35 mmol) and BnBr (1.49 mL, 12.52 mmol) in DMF (100 mL) at 0°C. The mixture was stirred at room temperature for 1 h, then brine (250mL) was added at 0° C. The aqueous layer was extracted with Et₂O (3×80mL). The combined organic layer was dried over MgSO₄ and concentratedunder reduced pressure. The material was purified on silica gel (80 gcartridge, 10-40% EtOAc in hexane) to provide the title compound (2.18g, 68%) as a sticky foam. LCMS m/z: ES⁺ [M+H]⁺: 384.18. (A05) retentiontime=2.77 min. ¹H NMR (400 MHz, cdcl3) δ 7.46-7.17 (m, 9H), 6.21 (d,J=6.0 Hz, 1H), 4.63 (d, J=13.0 Hz, 1H), 4.36 (d, J=15.9 Hz, 1H), 4.25(t, J=8.5 Hz, 1H), 4.13-3.99 (m, 1H), 3.83 (d, J=15.9 Hz, 1H), 2.16-2.04(m, 1H), 2.04-1.92 (m, 1H), 1.85 (d, J=16.9 Hz, 1H), 1.59-1.42 (m, 1H),1.24 (s, 9H).

Step 3(R)—N-benzyl-N—[(R)-[(2S)-6-hydroxy-5-iodo-tetrahydropyran-2-yl]-phenyl-methyl]-2-methyl-propane-2-sulfinamide

I₂ (1.59 g, 6.25 mmol) was added portionwise to a suspension of(R)—N-benzyl-N—[(R)-[(2S)-3,4-dihydro-2H-pyran-2-yl]-phenyl-methyl]-2-methyl-propane-2-sulfinamide(2.18 g, 5.68 mmol) and NaHCO₃ (1.43 g, 17.05 mmol) in ACN (25 mL) andH₂O (25 mL) at 0° C. The mixture was stirred at room temperature for 90min, then a saturated aqueous solution of Na₂S₂O₃ (10 mL) was added. Theaqueous layer was extracted with EtOAc (3×20 mL). The combined organiclayer was washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to provide the title compound.M+Na⁺m/z: 550.02 (A05), retention time=2.6 min.

Step 4 benzylN-benzyl-N—[(R)-[(2S)-6-hydroxy-5-iodo-tetrahydropyran-2-yl]-phenyl-methyl]carbamate

1 N HCl (11.3 mL, 11.36 mmol) was added to a mixture of(R)—N-benzyl-N-[(R)-[(2S)-6-hydroxy-5-iodo-tetrahydropyran-2-yl]-phenyl-methyl]-2-methyl-propane-2-sulfinamide(3.0 g, 5.68 mmol) in dioxane (80 mL). The mixture was stirred at roomtemperature for 20 min, LCMS indicated no starting material. Na₂CO₃ (4.8g, 45.44 mmol) and water (10 mL) was added. After 20 min, CbzCl (1.1 mL,7.95 mmol) was added dropwise. The mixture was stirred at roomtemperature overnight. Water (100 mL) was added. The separated aqueouslayer was extracted with EtOAc (3×50 mL). The combined organic layer waswashed with brine, dried over MgSO₄ and concentrated under reducedpressure. The material was purified on silica gel (80 g, dry loading) byMPLC using hexane to 60% EtOAc to provide the title compound (1.69 g,53%, over 3 steps) as a solid. [M+Na⁺]m/z: 580.04. (A05) retentiontime=˜2.8 min, several diastereomers.

Step 5 benzylN-[(R)-[(2S)-5-azido-6-oxo-tetrahydropyran-2-yl]-phenyl-methyl]-N-benzyl-carbamate

Dess-Martin Periodinane (1.93 g, 4.55 mmol) was added to a solution ofbenzylN-benzyl-N—[(R)-[(2S)-6-hydroxy-5-iodo-tetrahydropyran-2-yl]-phenyl-methyl]carbamate(1.69 g, 3.03 mmol, includes impurity) in DCM (100 mL) at 0° C. Themixture was stirred at room temperature for 5 h. Water (100 mL) wasadded following by a saturated aqueous solution of Na₂S₂O₃. Theseparated aqueous layer was extract with DCM (2×50 mL). The combinedorganic layer were washed with saturated aqueous NaHCO₃ (2×100 mL),brine (100 mL), dried over MgSO₄ and concentrated under reducedpressure.

The residue was taken in anhydrous DMF (75 mL) and NaN₃ (296 mg, 4.55mmol) was added. The mixture was stirred at room temperature for 15 min,then brine (300 mL) was added. The aqueous layer was extracted withEtOAc (3×100 mL). The combined organic layers was dried over MgSO₄ andconcentrated under reduced pressure. The material was purified on silicagel (40 g, dry loading) by MPLC using hexane to EtOAc to provide thetitle compound (603 mg, 42%) as an yellow oil. M+H⁺: 471 and/or M+Na493.

Step 6 BenzylN—[(R)-[(2S)-5-azido-6-hydroxy-tetrahydropyran-2-yl]-phenyl-methyl]-N-benzyl-carbamate

DIBAL-H (1 M in toluene, 7.65 mL, 7.65 mmol) was added dropwise to asolution of benzylN—[(R)-[(2S)-5-azido-6-oxo-tetrahydropyran-2-yl]-phenyl-methyl]-N-benzyl-carbamate(600 mg, complex mixture) in DCM (60 mL) at −78° C. After 1 h at −78°C., EtOH (0.5 mL) was added dropwise. The mixture was poured into asaturated aqueous solution of Rochelle's salt (300 mL). The mixture wasvigorously stirred for 1.5 h. The separated aqueous layer was extractedwith DCM (2×75 mL). The combined organic layer was washed with brine,dried over MgSO₄ and concentrated under reduced pressure. The residuewas purified on silica gel (24 g, dry loading) by MPLC using hexane to60% EtOAc in hexane to provide the title compound (482 mg, 72%). [M+H⁺]m/z: 473.11 retention time=2.71 min.

Step 7[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-[(2R,6S)-3-azido-6-[(R)-[benzyl(benzyloxycarbonyl)amino]-phenyl-methyl]tetrahydropyran-2-yl]oxy-cyclohexyl]acetate

CCl₃CN (0.44 mL, 4.39 mol) was added dropwise to a suspension of benzylN—[(R)-[(2S)-5-azido-6-hydroxy-tetrahydropyran-2-yl]-phenyl-methyl]-N-benzyl-carbamate(360 mg, 0.88 mmol) and K₂CO₃ (364 mg, 2.63 mmol) in dry DCM (10 mL) atambient temperature under N₂. The mixture was stirred at roomtemperature for 8 h, then filtered on celite and rinsed with DCM. Thefiltrate was concentrated under reduced pressure. The residue was takenin DCM (10 mL) and[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-hydroxy-cyclohexyl]acetate(654 mg, 2.19 mmol) was added. The mixture was cooled to −78° C., thenBF₃.OEt₂ (0.43 mL, 3.51 mmol) was added dropwise. The mixture wasstirred at room temperature for 5 h, then a saturated aqueous solutionof NaHCO₃ (50 mL) was added. The separated aqueous layer was extractedwith DCM (2×30 mL). The combined organic layer was washed with brine,dried over Na₂SO₄ and concentrated under reduced pressure. The residuewas purified on C18 silica (120 g Biotage) using 50% B in A to 100% B(B=ACN 0.1% HCOOH, A=H₂O 0.1% HCOOH); out at 90% to give the titleproducts (19 mg, 5%). LCMS m/z: ES⁺[M+H]⁺: 753.34. (A05) retentiontime=3.02 min.

Step 8 BenzylN—[(R)-[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]-phenyl-methyl]-N-benzyl-carbamate

NaOMe (4.62 M, 0.033 mL, 0.15 mmol) was added dropwise to a solution of[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-[(2R,6S)-3-azido-6-[(R)-[benzyl(benzyloxycarbonyl)amino]-phenyl-methyl]tetrahydropyran-2-yl]oxy-cyclohexyl]acetate(19 mg, 0.025 mmol) in MeOH (1 mL) at room temperature. After 60 min,AcOH (0.012 mL, 0.20 mmol) was added to the reaction and the mixture wasconcentrated under reduced pressure. HPLC provided the desired product(6 mg, 36%).

Step 9(1S,2R,3R,4S,6R)-4,6-diamino-3-[(2R,3R,6S)-3-amino-6-[(R)-amino(phenyl)methyl]tetrahydropyran-2-yl]oxy-cyclohexane-1,2-diol

Pd(OH)₂/C (10 wt %, 18.6 mg, 13.3 μmol) was added to a flask containingbenzylN—[(R)-[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]-phenyl-methyl]-N-benzyl-carbamate(6.0 mg, 89.7 μmol) under N₂ at ambient temperature. MeOH (3.0 mL) wasadded after which H₂ was bubbled through the suspension for 10 min.After 16 h under hydrogen atmosphere (1 atm, balloon), the solution wasfiltered through a frit (0.45 μm), rinsed with MeOH and the filtrate wasconcentrated under reduced pressure to give the title product (2.7 mg,82%). ¹H NMR (500 MHz, D₂O) δ 7.55-7.42 (m, 5H), 4.91 (s, 1H), 4.25-4.16(m, 1H), 4.10 (d, J=8.1 Hz, 1H), 3.40-3.34 (m, 1H), 3.21 (t, J=9.7 Hz,1H), 3.12 (s, 1H), 2.95-2.88 (m, 2H), 2.68 (t, J=8.7 Hz, 1H), 2.16-2.06(m, 1H), 2.05-1.95 (m, 1H), 1.90-1.67 (m, 3H), 1.20-1.08 (m, 1H).

Example 32(1S,2R,3R,4S,6R)-4,6-diamino-3-(((2R,3S,6S)-3-amino-6-((R)-amino(cyclopropyl)methyl)tetrahydro-2H-pyran-2-yl)oxy)cyclohexane-1,2-diol

Pd(OH)₂ (20 wt %, 133 mg, 190 μmol) was added to a solution of benzylN—[(R)-[(2S,5S,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]-cyclopropyl-methyl]-N-benzyl-carbamate(prepared in Example 9, 40.0 mg, 63.2 μmol) in MeOH (2.5 mL) and EtOH(2.5 mL). H₂ was bubbled through the suspension. After 17 h, thesolution was filtered through a frit (0.22 μm diameter) and the filtratewas concentrated under reduced pressure to give the desired product asan oil which turn into solid after lyophilization (19.0 mg, 91%). ¹H NMR(500 MHz, MeOD) δ 5.10 (s, 1H), 4.09-4.04 (m, 1H), 3.34-3.24 (m, 2H),3.07 (t, J=9.3 Hz, 1H), 3.01 (d, J=2.0 Hz, 1H), 2.83-2.71 (m, 1H), 2.66(ddd, J=12.1, 9.7, 4.1 Hz, 1H), 2.17-2.09 (m, 2H), 2.03 (d, J=13.0 Hz,1H), 1.99-1.86 (m, 2H), 1.74-1.63 (m, 1H), 1.60-1.48 (m, 1H), 1.00-0.82(m, 1H), 0.60 (dq, J=17.9, 8.8 Hz, 2H), 0.39-0.24 (m, 2H).

Example 33(1S,2R,3R,4S,6R)-4,6-diamino-3-(((2R,3S,6S)-3-amino-6-((R)-1-aminopropyl)tetrahydro-2H-pyran-2-yl)oxy)cyclohexane-1,2-diol

Pd(OH)₂/C (wet, 20 wt %, 249 mg, 354 μmol) was added to a solution ofbenzylN-[(1R)-1-[(2S,5S,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]propyl]-N-benzyl-carbamate(made in Example 5, 55.0 mg, 88.6 μmol) in MeOH (3.0 mL) and EtOH (3.0mL). H₂ was bubbled through the suspension. After 24 h, the solution wasfiltered through a frit (0.22 μm diameter) and the filtrate wasconcentrated under reduced pressure to give the desired product as anoil which turned into a solid after lyophilization (26.1 mg, 93%). ¹HNMR (500 MHz, MeOD) δ 4.97 (d, J=1.4 Hz, 1H), 3.91 -3.84 (m, 1H),3.19-3.08 (m, 2H), 2.95 (t, J=9.3 Hz, 1H), 2.89 (dd, J=5.8, 3.6 Hz, 1H),2.83-2.74 (m, 1H), 2.66 (ddd, J=12.2, 9.4, 4.3 Hz, 1H), 2.60-2.49 (m,1H), 1.99 -1.84 (m, 2H), 1.66-1.45 (m, 3H), 1.39-1.26 (m, 3H), 0.90 (t,J=7.5 Hz, 3H).

Example 34

Step 1(S)—N—[(S)-cyclopropyl-[(2S)-3,4-dihydro-2H-pyran-2-yl]methyl]-2-methyl-propane-2-sulfinamide

Cyclopropyl MgBr (0.5 M in THF, 55.7 mL, 27.8 mmol) was added to asolution of((NE,S)—N-[[(2S)-3,4-dihydro-2H-pyran-2-yl]methylene]-2-methyl-propane-2-sulfinamide(3.00 g, 13.9 mmol) in dry THF (100.0 mL) at −78° C. under N₂. After 1h, the reaction was stirred at −40° C. for 1 h and then warmed to roomtemperature within 1 h. After 1 h, the reaction was cooled to 0° C. andsat. NH₄Cl (100.0 mL) was added dropwise (CAUTION: gas evolution). THFwas evaporated under reduced pressure and then the mixture was extractedwith DCM (3×50 mL). The combined organic layers were dried (Na₂SO₄),filtered and concentrated under reduced pressure to provide the titlecompound as a liquid. The ¹H NMR for crude was clean and used in thenext step without further purification. ¹H NMR (500 MHz, CDCl₃) δ 6.37(d, J=6.1 Hz, 1H), 4.76 4.60 (m, 1H), 3.96-3.86 (m, 1H), 3.43 (d, J=6.1Hz, 1H), 2.56 (ddd, J=9.6, 6.2, 3.2 Hz, 1H), 2.19 1.75 (m, 4H), 1.22 (s,9H), 1.09-0.97 (m, 1H), 0.74-0.56 (m, 2H), 0.46-0.39 (m, 2H). LCMS m/zES⁺ [M+H]⁺: 258.19, LCMS (B05) retention time=1.78 m.

Step 2(S)—N-benzyl-N—[(S)-cyclopropyl(3,4-dihydro-2H-pyran-2-yl)methyl]-2-methyl-propane-2-sulfinamide

A mixture of(S)—N—[(S)-cyclopropyl(3,4-dihydro-2H-pyran-2-yl)methyl]-2-methyl-propane-2-sulfinamide(3.58 g, 13.9 mmol), bromomethylbenzene (2.97 mL, 25.0 mmol) in DMF(50.0 mL) was stirred at 0° C. NaH (0.667 g, 16.7 mmol) was then addedto the reaction mixture portionwise. The mixture was stirred at roomtemperature for 12 h. The reaction was quenched with water (100 mL) andthe mixture was extract with EtOAc (3×50 mL). The organic layers werecombined, washed with water and dried over sodium sulfate and thenconcentrated under reduced pressure. The residue was purified on silicagel (120 g) using hexane and ethylacetate (70/30) as eluent to give thetitle product (2.88 g, 60%) as an oil. LCMS m/z ES⁺[M+H]⁺: 348.16, LCMS(B05) retention time=2.10 m.

Step 3(S)—N-benzyl-N—[(S)-cyclopropyl-[(2S)-6-hydroxy-5-iodo-tetrahydropyran-2-yl]methyl]-2-methyl-propane-2-sulfinamide

I₂ (1.59 g, 6.30 mmol) was added portionwise to a suspension ofN-benzyl-N—[(S)-cyclopropyl-[(2S)-3,4-dihydro-2H-pyran-2-yl]methyl]-2-methyl-propane-2-sulfinamide(2.19 g, 6.30 mmol) and NaHCO₃ (1.58 g, 18.9 mmol) in ACN (38 mL) andH₂O (38 mL) at 0° C. The mixture was stirred at 0° C. for 15 min. Then,the mixture was stirred at room temperature for 15 min. Aftercompletion, a saturated aqueous solution of Na₂S₂O₃ (100 mL) was added.The aqueous layer was extracted with EtOAc (3×100 mL). The combinedorganic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure to provide the title compound (2.90 g, 94%) as anyellow solid. The crude was used in the next step without furtherpurification. LCMS m/z ES⁺ [M+Na]⁺: 514.50, LCMS (B05) retentiontime=2.10 and 2.21 m.

Step 4 BenzylN-benzyl-N—[(S)-cyclopropyl-[(2S)-6-hydroxy-5-iodo-tetrahydropyran-2-yl]methyl]carbamate

Aqueous HCl (1.0 M, 35.3 mL, 35.3 mmol) was dropwise added to a solutionofN-benzyl-N—[(S)-cyclopropyl-[(2S)-6-hydroxy-5-iodo-tetrahydropyran-2-yl]methyl]-2-methyl-propane-2-sulfinamide(2.88 g, 5.86 mmol) in dioxane (82.0 mL) with vigorous stirring. After 1h, solid Na₂CO₃ (4.96 g, 46.8 mmol) was added. After another 10 min,CbzCl (1.41 mL, 9.91 mmol) was added dropwise. After another 30-45 min,dioxane was evaporated and the residue was partitioned in between EtOAc(100.0 mL) and H₂O (100.0 mL). The organic phase was dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude was purifiedby silica gel chromatography (120 g cartridge) using hexanes and ethylacetate (0-30%) as eluent to give the title product (diastereomers, 1.50g, 49%) as an oil. LCMS m/z ES⁺[M+Na]⁺: 544.01, LCMS (B05) retentiontime=2.19 and 2.22 m.

Step 5 BenzylN—[(S)-[(2S)-5-azido-6-hydroxy-tetrahydropyran-2-yl]-cyclopropyl-methyl]-N-benzyl-carbamate

NaN₃ (0.561 g, 8.63 mmol) and K₂CO₃ (1.19 g, 8.63 mmol) was added to asolution of benzylN-benzyl-N—[(S)-cyclopropyl-[(2S)-6-hydroxy-5-iodo-tetrahydropyran-2-yl]methyl]carbamate(1.50 g, 2.87 mmol) in dry DMF (22.0 mL) under N₂ at ambienttemperature. After 4 h, the mixture was diluted with water (50.0 mL) andextracted with EtOAc (50.0 mL). The organic layer was dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude was purifiedby silica gel chromatography (40 g cartridge) with EtOAc and hexanes(10-30%) to produce the title compound (diastereomers) as an oil (0.80g, 63%). LCMS m/z: ES⁺[M+Na]⁺: 459.10; (B 05) retention time=2.16 m.

Step 6(1S,2S,3R,4S,6R)-4,6-diazido-3-(((2R,6S)-3-azido-6-(((S)-(benzyl((benzyloxy)carbonyl)amino)(cyclopropyl)methyl)tetrahydro-2H-pyran-2-yl)oxy)cyclohexane-1,2-diyldiacetate

CCl₃CN (0.567 mL, 5.66 mmol) was added dropwise to a suspension ofbenzylN—[(S)-[(2S)-5-azido-6-hydroxy-tetrahydropyran-2-yl]-cyclopropyl-methyl]-N-benzyl-carbamate(0.494 g, 1.13 mmol) and K₂CO₃ (0.469 g, 3.39 mmol) in dry DCM (20.0 mL)at ambient temperature under N₂. After 12 h, the solution was filteredthrough Celite and the filtrate was concentrated by high-vacuum. To thecrude was added[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-hydroxy-cyclohexyl]acetate(270 mg, 0.905 mmol) and ground 4 Å sieves (1.0 g) and the mixture wasdissolved in dry DCM (20.0 mL). The suspension was stirred at ambienttemperature for 30 min. The solution was cooled to 0° C. and BF₃OEt₂(0.559 mL, 4.53 mmol) was added dropwise with vigorous stirring. Thesolution was warmed to ambient temperature and stirred for another 2hours. The reaction was quenched with sat. NaHCO₃ (20.0 mL). The mixturewas successively extracted with DCM (3×20 mL) and the combined organiclayer were dried (Na₂SO₄), filtered and concentrated under reducedpressure. The crude was purified by silica gel chromatography (40 gcartridge) with EtOAc and hexanes (0-30%) to produce the title compoundas an oil (diastereomers, 0.510 mg, 79%). LCMS m/z: [M+H]⁺: 716.97;(B05) retention time=2.39 m.

Step 7 BenzylN-[(S)-[(2S,5S,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]-cyclopropyl-methyl]-N-benzyl-carbamate

NaOMe (4.62 M, 924 μL, 4.27 mmol) was added dropwise to a solution of(1S,2S,3R,4S,6R)-4,6-diazido-3-(((2R,6S)-3-azido-6-((S)-(benzyl((benzyloxy)carbonyl)amino)(cyclopropyl)methyl)tetrahydro-2H-pyran-2-yl)oxy)cyclohexane-1,2-diyldiacetate (0.510 g, 0.712 mmol) in MeOH (30.0 mL) at room temperature.After 60 min, AcOH (326 μL, 5.69 mmol) was added to the reaction. Water(20.0 mL) was added and the mixture was extracted with DCM (3×30 mL).The organic layers were combined, dried over Na₂SO₄ and thenconcentrated under reduced pressure to provide a mixture of twodiastereomers (0.350 g, 78%) in a 7:1 ratio in favor of the transproduct (see note for more details). ES⁺[M+Na]⁺: 655.06; (B05) retentiontime=2.23 m.

Step 8(1S,2R,3R,4S,6R)-4,6-diamino-3-(((2R,3S,6S)-3-amino-6-((S)-amino(cyclopropyl)methyl)tetrahydro-2H-pyran-2-yl)oxy)cyclohexane-1,2-diol

Pd(OH)₂/C (20 wt %, 300 mg, 427 μmol) was added to a solution of benzylN—[(S)-[(2S,5S,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]-cyclopropyl-methyl]-N-benzyl-carbamate(45.0 mg, 71.1 μmol) in MeOH (2.5 mL) and EtOH (2.5 mL). H₂ was bubbledthrough the suspension. After 24 h, the solution was filtered through afrit (0.22 μm diameter) and the filtrate was concentrated under reducedpressure to give the desired product as an oil which turn into solidafter lyophilization (20.0 mg, 85%). ¹H NMR (500 MHz, MeOD) δ 5.34 (s,1H), 4.24-4.19 (m, 1H), 3.40-3.35 (m, 2H), 3.15 (t, J=9.3 Hz, 1H), 3.06(d, J=1.6 Hz, 1H), 2.92-2.84 (m, 1H), 2.79 (ddd, J=12.1, 9.9, 4.2 Hz,1H), 2.52-2.40 (m, 2H), 2.20-2.11 (m, 1H), 2.10-2.03 (m, 1H), 1.99-1.88(m, 1H), 1.78-1.69 (m, 1H), 1.60-1.51 (m, 1H), 1.15-1.05 (m, 1H),0.79-0.63 (m, 2H), 0.46-0.36 (m, 2H).

Example 35(1S,2R,3R,4S,6R)-4,6-diamino-3-[(2R,3S,6S)-3-amino-6-[(1S)-1-aminopropyl]tetrahydropyran-2-yl]oxy-cyclohexane-1,2-diol

In a round bottom flask equipped with a reflux condenser were addedbenzylN-[(1S)-1-[(2S,5S,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]propyl]-N-benzyl-carbamate(made in Example 4, 38.0 mg, 0.0612 mmol) and Pd/C (10% dry on carbon,19.5 mg, 0.0184 mmol) following by anhydrous MeOH (6.00 mL). Nitrogenwas bubbled for 5 min, then ammonium format was added. The mixture washeat at 63° C. for 30 min under N₂, then cooled to room temperature withan ice-bath. The mixture was filtered through a fritted funnel and thenconcentrated under reduced pressure to give the titled product as aliquid which then lyophilized to give a solid (11.1 mg, 57%). LCMS m/z:ES⁺[M+Na]⁺:341, (A05) retention time=0.97 m. ¹H NMR (400 MHz, CD₃OD) δ5.09 (s, 1H), 4.00 (d, J=10.8 Hz, 1H), 3.35-3.20 (m, 2H), 3.15-2.97 (m,2H), 2.93-2.58 (m, 3H), 2.19-1.97 (m, 2H), 1.86-1.58 (m, 4H), 1.56-1.36(m, 2H), 1.06 (t, J=7.4 Hz, 3H).

Example 36

Step 1 (R)—N-[(1S)-1-[(2S)-3,4-dihydro-2H-pyran-2-yl]-2-[isopropoxy(dimethyl)silyl]ethyl]-2-methyl-propane-2-sulfinamide

A suspension of magnesium filings (4.85 g, 199 mmol) in dry THF (125 mL)was heated at 65° C. with high agitation under an atmosphere ofnitrogen. 1,2-Dibromoethane (0.52 mL, 6 mmol) was added over 1 min,followed by slow addition of chloromethyl dimethylisopropoxysilane (25g, 150 mmol) over 15 min. The reaction was stirred at 65° C. for 90 min,then cooled to room temperature to give 1 M solution which was kept in afreezer (maximum 2 weeks).

To a solution of(NE,R)—N-[[(2S)-3,4-dihydro-2H-pyran-2-yl]methylene]-2-methyl-propane-2-sulfinamide(10 g, 46.4 mmol) in DCM (600 mL) was added dropwisechloro-[[isopropoxy(dimethyl)silyl]methyl]magnesium (1 M in THF, 93 mL,93 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 1 h,then warmed to room temperature and stirred for 3 h. The mixture wasdiluted with saturated NaHCO₃ (400 mL) and the layers were separated.The aqueous layer was extracted with DCM (3×300 mL). The combinedorganic layers were washed with brine, dried (MgSO₄), filtered andconcentrated under reduced pressure to provide the title compound (11 g,68%). ¹H-NMR (400 MHz, CDCl₃) δ 6.36 (d, J=6.1 Hz, 1H), 4.69-4.63 (m,1H), 4.04 (ddd, J=11.1, 3.5, 1.9 Hz, 1H), 3.97 (dt, J=12.1, 6.1 Hz, 1H),3.90 (d, J=7.3 Hz, 1H), 3.61 (ddd, J=14.6, 7.3, 3.6 Hz, 1H), 2.14-2.03(m, 1H), 2.00-1.91 (m, 1H), 1.89-1.81 (m, 1H), 1.70-1.55 (m, 1H), 1.21(s, 9H), 1.13 (d, J=3.3 Hz, 3H), 1.12 (d, J=3.3 Hz, 3H), 0.83 (dd,J=15.0, 6.8 Hz, 1H), 0.15 (d, J=2.8 Hz, 3H), 0.13 (s, 3H). (NH was notobserved) MS (ESI) [M+Na]⁺370.1.

Step 2(R)—N-[(1R)-1-[(2S)-3,4-dihydro-2H-pyran-2-yl]-2-hydroxy-ethyl]-2-methyl-propane-2-sulfinamide

To a solution of(R)—N-[(1S)-1-[(2S)-3,4-dihydro-2H-pyran-2-yl]-2-[isopropoxy(dimethyl)silyl]ethyl]-2-methyl-propane-2-sulfinamide(11 g, 3.16 mmol) in MeOH (600 mL) was added KF (3.11 g, 3.64 mmol) andNaHCO₃ (3.19 g, 38 mmol). H₂O₂ (35% wt in water, 5.44 mL, 63.3 mL) wasadded dropwise over 5 min and the reaction mixture was stirred at roomtemperature for 16 h. The mixture was diluted with saturated solution ofNa₂S₂O₃ (400 mL) and the aqueous layer was extracted with EtOAc (3×600mL). The combined organic layers were washed with brine (1.0 L), dried(MgSO₄), filtered and concentrated under reduced pressure to provide thetitle compound (7.9 g, 99%) as an oil. ¹H NMR (500 MHz, CDCl₃) δ 6.34(d, J=6.4 Hz, 1H), 4.75-4.70 (m, 1H), 4.09 (ddd, J=10.5, 5.6, 1.7 Hz,1H), 3.94 (d, J=7.6 Hz, 1H), 3.87-3.82 (m, 1H), 3.80-3.74 (m, 1H),3.44-3.37 (m, 1H), 2.65 (dd, J=9.2, 4.3 Hz, 1H), 2.15-2.06 (m, 1H),2.03-1.98 (m, 1H), 1.74-1.66 (m, 1H), 1.26 (s, 9H).

Step 3(R)—N-benzyl-N-[(1R)-2-benzyloxy-1-[(2S)-3,4-dihydro-2H-pyran-2-yl]ethyl]-2-methyl-propane-2-sulfinamide

To a solution of BnBr (4.90 mL, 41.2 mmol) and(R)—N-[(1R)-1-[(2S)-3,4-dihydro-2H-pyran-2-yl]-2-hydroxy-ethyl]-2-methyl-propane-2-sulfinamide(3.40 g, 13.7 mmol) in DMF (120 mL) at 0° C., was added NaH (60% oildispersion, 1.15 g, 28.9 mmol). The reaction mixture was stirred at 0°C. for 1 h, then brine (500 mL) was added at 0° C. The aqueous layer wasextracted with Et₂O (3×150 mL). The combined organic layers were dried(MgSO₄), filtered and concentrated under reduced pressure. The materialwas purified by silica gel (80 g, dry loading) by MPLC using a gradientof 0-50% EtOAc in hexane as eluent to provide the title compound (2.30g, 39%) as a solid. MS (ESI) [M+Na]⁺450.1.

Step 4 BenzylN-benzyl-N-[(1R)-2-benzyloxy-1-[(2S)-6-hydroxy-5-iodo-tetrahydropyran-2-yl]ethyl]carbamate

To a solution of(R)—N-benzyl-N-[(1R)-2-benzyloxy-1-[(2S)-3,4-dihydro-2H-pyran-2-yl]ethyl]-2-methyl-propane-2-sulfinamide(2.30 g, 5.38 mmol) and NaHCO₃ (1.36 g, 16.1 mmol) in ACN (100 mL) andwater (100 mL) at 0° C., was added 12 (1.50 g, 5.92 mmol). The reactionmixture was stirred at 0° C. for 45 min, then a saturated solution ofNa₂S₂O₃ (200 mL) was added following by EtOAc (250 mL). The layers wereseparated, and the aqueous layer was extracted with EtOAc (3×150 mL).The combined organic layers were washed with brine (500 mL), dried(MgSO₄), filtered and concentrated under reduced pressure. The residuewas taken in dioxane (50 mL) and 2M HCl (8.07 mL, 16.1 mmol) was addeddropwise. The mixture was stirred at room temperature for 30 min, thenNa₂CO₃ (3.42 g, 32.3 mmol) was added. After 10 min at room temperature,CbzCl (1.54 mL, 10.7 mmol) was added dropwise. The mixture was stirredat room temperature for 2 h, then water (100 mL) was added. The aqueouslayer was extracted with EtOAc (3×100 mL). The combined organic layerswere washed with brine, dried (MgSO₄), filtered and concentrated underreduced pressure. The material was purified by silica gel (120 g, dryloading) by MPLC using a gradient of 0-50% EtOAc in hexane as eluent toprovide the title compound (2.40 g, 74% over 3 steps) as a solid. MS(ESI) [M+H]⁺602.4.

Step 5 benzylN-[(1R)-1-[(2S)-5-azido-6-oxo-tetrahydropyran-2-yl]-2-benzyloxy-ethyl]-N-benzyl-carbamate

To a mixture of benzylN-benzyl-N—[(1R)-2-benzyloxy-1-[(2S)-6-hydroxy-5-iodo-tetrahydro-pyran-2-yl]ethyl]carbamate(2.40 g, 3.99 mmol) and 4 Å molecular sieves (1.00 g) in DCM (150 mL)was added PDC (6.76 g, 18.0 mmol) at room temperature. After 18 h, themixture was filtered on silica pad, rinsed with EtOAc and concentratedunder reduced pressure. The residue was taken in DMF (25 mL) and cooledat 0° C. NaN₃ (285 mg, 4.39 mmol) was added and the mixture was stirredfor 1 h at 0° C. The mixture was diluted with brine (250 mL) and theaqueous layer was extracted with Et₂O (3×150 mL). The combined organiclayers were dried (MgSO₄), filtered and concentrated under reducedpressure. The residue was purified by silica (40 g, dry loading) by MPLCusing a gradient of 0-40% EtOAc in hexane as eluent to provide the titlecompound (450 mg, 22% over 2 steps) as a solid. MS (ESI) [M+H]⁺515.2.

Step 6 BenzylN-[(1R)-1-[(2S,5R)-5-azido-6-hydroxy-tetrahydropyran-2-yl]-2-benzyloxy-ethyl]-N-benzyl-carbamate

To a solution of benzylN-[(1R)-1-[(2S)-5-azido-6-oxo-tetrahydropyran-2-yl]-2-benzyloxy-ethyl]-N-benzyl-carbamate(400 mg, 0.78 mmol) in DCM (18 mL) at −78° C., DIBAL-H (1M in toluene,1.55 mL, 1.55 mmol) was added dropwise and the reaction mixture wasstirred for 1 h. EtOH (0.5 mL) was added dropwise and the mixture waspoured into a saturated solution of Rochelle's salt (300 mL). Themixture was vigorously stirred for 1 h at room temperature. The aqueouslayer was extracted with DCM (2×75 mL). The combined organic layers werewashed with brine, dried (MgSO₄) and concentrated under reducedpressure. The residue was purified by silica gel (40 g, dry loading) byMPLC using a gradient of 0-40% EtOAc in hexane as eluent to providebenzylN-[(1R)-1-[(2S,5S)-5-azido-6-hydroxy-tetrahydropyran-2-yl]-2-benzyloxy-ethyl]-N-benzyl-carbamate(96 mg, 24%) and the desired diastereoisomer benzylN-[(1R)-1-[(2S,5R)-5-azido-6-hydroxy-tetrahydropyran-2-yl]-2-benzyloxy-ethyl]-N-benzyl-carbamate(188 mg, 47%) as an oil. MS (ESI) [M+H]⁺517.3.

Step 7 BenzylN-[(1R)-1-[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]-2-benzyloxy-ethyl]-N-benzyl-carbamate

To a mixture of benzylN-[(1R)-1-[(2S,5R)-5-azido-6-hydroxy-tetrahydropyran-2-yl]-2-benzyloxy-ethyl]-N-benzyl-carbamate(188 mg, 0.36 mmol) and K₂CO₃ (352 mg, 2.55 mmol) in dry DCM (10 mL) atroom temperature was added CCl₃CN (0.29 mL, 2.91 mmol). The mixture wasstirred at room temperature for 16 h, then filtered on celite and rinsedwith DCM. The filtrate was concentrated under reduced pressure. Theresidue was taken in anhydrous DCM (10 mL) and[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-hydroxy-cyclohexyl]acetate(239 mg, 0.80 mmol) was added. The mixture was cooled to −78° C., thenBF₃.OEt₂ (0.14 mL, 1.13 mmol) was added dropwise. The reaction mixturewas warmed to 0° C. and stirred for 1 h. The mixture was diluted withsaturated NaHCO₃ (50 mL) and the aqueous layer was extracted with DCM(2×30 mL). The combined organic layers were washed with brine, dried(Na₂SO₄), filtered and concentrated under reduced pressure. The residuewas taken in MeOH (10 mL) and NaOMe (4.62 M in MeOH, 0.55 mL, 2.55 mmol)was added. The reaction mixture was stirred at room temperature for 2 h,then concentrated under reduced pressure. The residue was diluted withDCM (20 mL) and saturated NH₄Cl (80 mL). The layers were separated, andthe aqueous layer was extracted with DCM (2×30 mL). The combined organiclayers were washed with brine, dried (Na₂SO₄), filtered and concentratedunder reduced pressure. The material was purified by reverse phasechromatography (C18) using a gradient of 5-100% ACN in water (contains0.1% formic acid) to provide the title compound (134 mg, 52% over 3steps) as a solid. MS (ESI) [M+H]⁺713.3.

Step 8(1S,2R,3R,4S,6R)-4,6-diamino-3-[(2R,6S)-3-amino-6-[(1R)-1-amino-2-hydroxy-ethyl]tetrahydropyran-2-yl]oxy-cyclohexane-1,2-diolformate

In a 2 neck flask equipped with a reflux condenser were added(1S,2R,3R,4S,6R)-4,6-diazido-3-(((2R,3R,6S)-3-azido-6-((R)-1-(benzyl(methyl)amino)-2-(benzyloxy)ethyl)tetrahydro-2H-pyran-2-yl)oxy)cyclohexane-1,2-diol(16 mg, 0.02 mmol) and Pd/C (10% dry on carbon, 7.2 mg, 0.01 mmol)followed by MeOH (5 mL). Nitrogen was bubbled for 5 min, then ammoniumformate (15.6 mg, 0.25 mmol) was added. The mixture was heated at 63° C.for 3 h under N₂. The mixture was cooled with an ice-bath and thenfiltered with a filter syringe and the filtrate was concentrated underreduced pressure. The material was purified by preparative HPLC (WatersX-Bridge C18 30×150 mm; Flow rate: 40 mL/min) using a gradient of 10-25%ACN in Amfor pH 3.8 over 7 min to provide the title compound (3.90 mg,34%) as a solid. ¹H-NMR (400 MHz, CD₃OD) δ 8.45 (br, 4H), 5.64 (s, 1H),4.27-4.17 (m, 1H), 3.84-3.69 (m, 3H), 3.62-3.55 (m, 1H), 3.51-3.44 (m,1H), 3.40-3.31 (m, 2H), 3.16-3.02 (m, 3H), 2.35-2.21 (m, 1H), 1.97-1.92(m, 1H), 1.86-1.80 (m, 1H), 1.66-1.57 (m, 2H). MS (ESI) [M+H]⁺321.4.

Example 37

(1S,2R,3R,4S,6R)-3-[(2R,3R,6S)-6-(aminomethyl)-3-hydroxy-tetrahydropyran-2-yl]oxy-4,6-diazido-cyclohexane-1,2-diol

Pd(OH)₂ (20 wt %, 129 mg, 0.183 mmol) was added to a solution of benzylN-benzyl-N-[[(2S,5R,6R)-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]-5-hydroxy-tetrahydropyran-2-yl]methyl]carbamate(see Example 15 for synthesis, 26.0 mg, 45.8 μmol) in MeOH (2.50 mL) andEtOH (2.50 mL). H₂ was bubbled and the suspension was hydrogenated underhydrogen atmosphere for 12 h. The suspension was filtered through a frit(0.22 μm diameter) and the filtrate was concentrated under reducedpressure to afford the title compound (13.0 mg, 97%) as a solid. ¹H NMR(400 MHz, MeOD) δ 5.17 (d, J=3.4 Hz, 1H), 4.07-3.97 (m, 1H), 3.72 (ddd,J=11.4, 5.1, 3.6 Hz, 1H), 3.47 (t, J=9.2 Hz, 1H), 3.28 (t, J=9.5 Hz,1H), 3.17 (t, J=9.4 Hz, 1H), 2.90 (ddd, J=23.0, 12.6, 3.8 Hz, 2H),2.82-2.70 (m, 2H), 2.09 (dt, J=12.7, 4.1 Hz, 1H), 1.94-1.69 (m, 4 H),1.30 (q, J=12.5 Hz, 1H). MS (ESI) [M+H]⁺325.2.

Example 38

(1S,2R,3R,4S,6R)-4,6-diamino-3-[(2R,3S,4S,5R,6R)-3-amino-6-(aminomethyl)-4-fluoro-5-hydroxy-tetrahydropyran-2-yl]oxy-cyclohexane-1,2-diol

Pd(OH)₂ (20 wt %, 105 mg, 0.149 mmol) was added to a solution of(1S,2R,3R,4S,6R)-4,6-diazido-3-(((2R,3S,4S,5R,6R)-3-azido-6-(azidomethyl)-4-fluoro-5-hydroxytetrahydro-2H-pyran-2-yl)oxy)cyclohexane-1,2-diol(see Example 22 for synthesis, 20.0 mg, 49.7 μmol) in MeOH (2.0 mL) andEtOH (2.0 mL). H₂ was bubbled and the suspension was hydrogenate underhydrogen atmosphere for 12 h. The mixture was filtered through a frit(0.22 μm diameter) and the filtrate was concentrated under reducedpressure to afford the title compound (12.9 mg, 80%) as a solid.¹HNMR(500 MHz, MeOD) δ 5.48 (d, J=4.6 Hz, 1H), 4.78 (t, J=53.0, 2.2 Hz,1H), 4.01 (ddd, J=10.5, 5.5, 2.1 Hz, 1H), 3.56-3.44 (m, 2H), 3.31 (t,J=9.3 Hz, 1H), 3.22 (dd, J=13.2, 2.9 Hz, 1H), 3.16 (t, J=9.5 Hz, 1H),3.05 (ddd, J=33.9, 4.6, 2.5 Hz, 1H), 2.95-2.84 (m, 2H), 2.77 (ddd,J=12.1, 9.8, 4.2 Hz, 1H), 2.07 (dt, J=12.8, 4.2 Hz, 1H), 1.32 (dd,J=24.8, 12.3 Hz, 1H).

Example 39

Step 1 BenzylN-[[(5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2-hydroxy-3-methoxy-cyclohexoxy]tetrahydropyran-2-yl]methyl]-N-benzyl-carbamate

Me₂SO₄ (51 μL, 68 mmol) was added to a vigorously stirring suspension ofbenzylN-[[(5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]methyl]-N-benzyl-carbamate(see Example 11 for synthesis, 40 mg, 67 μmol) and TBAI (4 mg, 10 μmol)in a mixture DCM (1.0 mL) and NaOH solution (1.0 M aq., 1.0 mL, 1.0mmol) at ambient temperature. After 2 h, concentrated NH₄OH (200 μL) wasadded and the mixture was partitioned in between water (10.0 mL) and DCM(10.0 mL). The aqueous layer was extracted with DCM (5.0 mL) and thecombined organic layers were dried (Na₂SO₄), filtered and concentratedunder reduced pressure. The material was purified by silica gelchromatography (12 g cartridge) using a gradient of 10-40% EtOAc inhexane as eluent and was further purified by preparative HPLC (BEH30×150 mm C18 ACN/AmForm 70-80%) to provide the title compound(rotamers, 16 mg, 39%) as a solid. ¹H NMR (400 MHz, CDCl₃) δ 7.48-7.04(m, 10H), 5.32-5.04 (m, 3H), 4.72 (d, J=15.9 Hz, 1H), 4.47 (d, J=16.0Hz, 1H), 4.34-4.12 (m, 1H), 3.66 (s, 3H), 3.59-3.10 (m, 8H), 2.96 (t,J=9.5 Hz, 1H), 2.19 (dt, J=13.2, 4.5 Hz, 1H), 2.06-1.92 (m, 1H),1.92-1.81 (m, 1H), 1.73-1.51 (m, 1H), 1.47-1.28 (m, 2H). MS ESI[M+H]⁺607.2.

Step 2(1R,2R,3S,5R,6S)-3,5-diamino-2-[(2R,3R,6S)-3-amino-6-(aminomethyl)tetrahydropyran-2-yl]oxy-6-methoxy-cyclohexanol,formic acid

Pd(OH)₂ (10 wt %, 9.3 mg, 6.6 μmol) was added to a solution of benzylN-[[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2-hydroxy-3-methoxy-cyclohexoxy]tetrahydropyran-2-yl]methyl]-N-benzyl-carbamate(16 mg, 26.4 μmol) in MeOH (1.5 mL) under N₂ at ambient temperature. H₂was bubbled through the suspension for 15 min and then the suspensionwas stirred for 18 h. The solution was filtered through a frit (0.22 μmdiameter) and the filtrate was concentrated under reduced pressure. Thematerial was purified by preparative HPLC (BEH 30×150 mm C18 ACN/AmForm10-25%) to provide the title compound (9 mg, 70%). ¹H NMR (500 MHz, D₂O)δ 8.53 (s, 3H), 5.79 (d, J=3.3 Hz, 1H), 4.26-4.16 (m, 1H), 3.96 (t,J=9.8 Hz, 1H), 3.82 (t, J=8.8 Hz, 1H), 3.64 (s, 3H), 3.62-3.53 (m, 1H),3.53-3.44 (m, 1H), 3.43-3.35 (m, 2H), 3.27 (dd, J=13.5, 3.2 Hz, 1H),3.12 (dd, J=13.6, 7.3 Hz, 1H), 2.50 (dt, J=5.5, 3.1 Hz, 1H), 2.11-1.98(m, 2H), 1.98-1.82 (m, 2H), 1.70-1.57 (m, 1H). MS ESI [M+H]⁺350.2

Example 40

Step 1(S)—N-[(1R)-1-[(2S)-3,4-dihydro-2H-pyran-2-yl]-2-[isopropoxy(dimethyl)silyl]ethyl]-2-methyl-propane-2-sulfinamide

A suspension of magnesium filings (4.85 g, 199 mmol) in dry THF (125 mL)was heated at 65° C. with high agitation under an atmosphere ofnitrogen. 1,2-Dibromoethane (0.52 mL, 6 mmol) was then added over 1 min,followed by slow addition of chloromethyl dimethylisopropoxysilane (25g, 150 mmol) over 15 min. The mixture was stirred at 65° C. for 90 min,then cooled to room temperature to give a 1 M solution ofChloro-[[isopropoxy(dimethyl)silyl]methyl] in THF.

Chloro-[[isopropoxy(dimethyl)silyl]methyl]magnesium (1M in THF, 86 mL,86 mmol) was added dropwise to a solution of(NE,S)—N-[[(2S)-3,4-dihydro-2H-pyran-2-yl]methylene]-2-methyl-propane-2-sulfinamide(9.30 g, 43.2 mmol) in DCM (500 mL) at −78° C. The mixture was stirredat −78° C. for 3 h, then warmed to room temperature. A saturatedsolution of NaHCO₃ (400 mL) was added and the separated aqueous layerwas extracted with DCM (3×). The combined organic layers were washedwith brine, then dried (MgSO₄) and concentrated under reduced pressureto afford the title compound (15 g, 99%), which was used in the nextstep without further purification. MS (ESI) [M+Na]⁺370.4.

Step 2(S)—N-[(1S)-1-[(2S)-3,4-dihydro-2H-pyran-2-yl]-2-hydroxy-ethyl]-2-methyl-propane-2-sulfinamide

To a solution of(S)—N-[(1R)-1-[(2S)-3,4-dihydro-2H-pyran-2-yl]-2-[isopropoxy(dimethyl)silyl]ethyl]-2-methyl-propane-2-sulfinamide(15.0 g, 43.2 mmol) in a mixture of THF (600 mL) and MeOH (600 mL), wasadded KF (2.88 g, 49.6 mmol) and NaHCO₃ (4.35 g, 51.8 mmol). The mixturewas cooled to 5° C. and a solution of H₂O₂ (7.42 mL 30 wt % H₂O₂; 86.3mmol) was added dropwise. The reaction mixture was warmed roomtemperature and was stirred for 16 h. The mixture was quenched withsaturated Na₂S₂O₃ (˜250 mL) and diluted with saturated NaHCO₃ (˜100 mL).The aqueous layer was extracted with EtOAc (2.5 L). The organic phasewas dried (MgSO₄), filtered and concentrated under reduced pressure. Thecrude oil was diluted with ether (1.5 L) and washed with brine (500 mL).The organic layer was dried (Na₂SO₄), filtered and concentrated underreduced pressure to afford the title compound (8.31 g, 78%). MS (ESI)[M+H]⁺248.3.

Step 3(S)—N-benzyl-N-[(1S)-2-benzyloxy-1-[(2S)-3,4-dihydro-2H-pyran-2-yl]ethyl]-2-methyl-propane-2-sulfinamide

NaH (60%, 1.15 g, 28.9 mmol) was added to a mixture of BnBr (4.90 mL,41.2 mmol) and(S)—N-[(1S)-1-[(2S)-3,4-dihydro-2H-pyran-2-yl]-2-hydroxy-ethyl]-2-methyl-propane-2-sulfinamide(3.40 g, 13.7 mmol) in DMF (100 mL) at 0° C. The reaction mixture wasstirred at 0° C. for 1 h, then brine (500 mL) was added. The separatedaqueous layer was extracted with EtOAc (3×150 mL). The combined organiclayers were dried (Na₂SO₄), filtered and concentrated under reducedpressure. The material was purified by flash chromatography (120 g, dryloading) using a gradient of 5-45% EtOAc in hexane as eluent to providethe title compound (5.11 g, 87%). MS (ESI) [M+Na]⁺450.4.

Step 4 BenzylN-benzyl-N-[(1S)-2-benzyloxy-1-[(2S)-6-hydroxy-5-iodo-tetrahydropyran-2-yl]ethyl]carbamate

I₂ (3.34 g, 13.1 mmol) was added to a mixture of(R)—N-benzyl-N-[(1S)-2-benzyloxy-1-[(2S)-3,4-dihydro-2H-pyran-2-yl]ethyl]-2-methyl-propane-2-sulfinamide(5.11 g, 12.0 mmol) and NaHCO₃ (3.01 g, 35.9 mmol) in a mixture ACN (100mL) and water (100 mL) at 0° C. The reaction mixture was stirred at 0°C. for 45 min, then a saturated aqueous solution of Na₂S₂O₃ (200 mL) wasadded. The aqueous layer was extracted with EtOAc (3×150 mL). Thecombined organic layer was washed with brine (500 mL), then dried(Na₂SO₄), filtered and concentrated under reduced pressure to afford(S)—N-benzyl-N-((1S)-2-(benzyloxy)-1-((2S)-6-hydroxy-5-iodotetrahydro-2H-pyran-2-yl)ethyl)-2-methylpropane-2-sulfinamide.

To the above material(S)—N-benzyl-N-((1S)-2-(benzyloxy)-1-((2S)-6-hydroxy-5-iodotetrahydro-2H-pyran-2-yl)ethyl)-2-methylpropane-2-sulfinamidewas taken in dioxane (50 mL), was added aqueous solution of 1 N HCl(17.9 mL, 17.9 mmol) dropwise and the reaction mixture was stirred atroom temperature for 30 min. Na₂CO₃ (7.60 g, 71.7 mmol) was then addedand the mixture was stirred for 10 min. CbzCl (3.41 mL, 23.9 mmol) wasadded dropwise and the reaction mixture was stirred at room temperaturefor 2 h. The mixture was diluted with water (100 mL) and the separatedaqueous layer was extracted with EtOAc (3×100 mL). The combined organiclayers were washed with brine, then dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The material was purified by flashchromatography (120 g, dry loading) using a gradient of 0-50% EtOAc inhexane as eluent to provide the title compound (4.10 g, 57% over 3steps). MS (ESI) [M+Na]⁺624.3.

Step 5 BenzylN-[(1S)-1-[(2S,5R)-5-azido-6-oxo-tetrahydropyran-2-yl]-2-benzyloxy-ethyl]-N-benzyl-carbamate

To a solution of benzylN-benzyl-N-[(1S)-2-benzyloxy-1-[(2S)-6-hydroxy-5-iodo-tetrahydropyran-2-yl]ethyl]carbamate(4.10 g, 6.82 mmol) in DCM (200 mL), was added 4 Å molecular sieves(2.00 g), and then PDC (11.5 g, 30.7 mmol) and the suspension wasstirred at room temperature for 18 h. The mixture was filtered on asilica pad, rinsed with EtOAc and concentrated under reduced pressure.

To the above material in DMF (30 mL) at 0° C., was added NaN₃ (0.49 g,7.50 mmol) and the reaction mixture was stirred for 1 h at roomtemperature. The mixture was diluted with brine (250 mL) and theseparated aqueous layer was extracted with Et₂O. The combined organiclayers were dried (Na₂SO₄), filtered and concentrated under reducedpressure. The material was purified by flash chromatography (40 g, dryloading) using a gradient of 0-50% EtOAc in hexane as eluent to providethe title compound (first eluting, 350 mg, 10%) along with benzyl((S)-1-((2S,5S)-5-azido-6-oxotetrahydro-2H-pyran-2-yl)-2-(benzyloxy)ethyl)(benzyl)carbamate(second eluting, 335 mg). MS (ESI) [M+H]⁺515.4.

Step 6 BenzylN-[(1S)-1-[(2S,5R)-5-azido-6-hydroxy-tetrahydropyran-2-yl]-2-benzyloxy-ethyl]-N-benzyl-carbamate

DIBAL-H (1 M in toluene, 1.36 mL, 1.36 mmol) was added dropwise to asolution of benzylN-[(1S)-1-[(2S,5R)-5-azido-6-oxo-tetrahydropyran-2-yl]-2-benzyloxy-ethyl]-N-benzyl-carbamate(350 mg, 0.68 mmol) in DCM (20 mL) at −78° C. After 1 h at −78° C., EtOH(1 mL) was added dropwise and the mixture was poured into a saturatedaqueous solution of Rochelle's salt (300 mL). The mixture was vigorouslystirred for 1 h and the separated aqueous layer was extracted with DCM(2×75 mL). The combined organic layers were washed with brine, thendried (Na₂SO₄), filtered and concentrated under reduced pressure. Thematerial was purified by flash chromatography (40 g, dry loading) usinga gradient of 5-40% EtOAc in hexane to provide the title compound (334mg, 95%) as an oil. MS (ESI) [M+Na]⁺539.3.

Step 7 BenzylN-[(1S)-1-[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]-2-benzyloxy-ethyl]-N-benzyl-carbamate

CCl₃CN (0.45 mL, 4.50 mmol) was added dropwise to a suspension of benzylN-[(1S)-1-[(2S,5R)-5-azido-6-hydroxy-tetrahydropyran-2-yl]-2-benzyloxy-ethyl]-N-benzyl-carbamate(334 mg, 0.65 mmol) and K₂CO₃ (544 mg, 3.94 mmol) in dry DCM (10 mL) atroom temperature. The mixture was stirred at room temperature for 18 h,then filtered on Celite and rinsed with DCM. The filtrate wasconcentrated under reduced pressure to afford(3R,6S)-3-azido-64(S)-1-(benzyl((benzyloxy)carbonyl)amino)-2-(benzyloxy)ethyl)tetrahydro-2H-pyran-2-yl2,2,2-trichloroacetimidate, which was used in the next step withoutfurther purification.

To a solution of above material in anhydrous DCM (10 mL),[(1S,2S,3R,4S,6R)-2-acetoxy-4,6-diazido-3-hydroxy-cyclohexyl]acetate(168 mg, 0.56 mmol) was added followed activated molecular sieve and thereaction mixture was stirred for 2 h. The mixture was cooled to −78° C.,and then BF₃.Et₂O (0.22 mL, 1.74 mmol) was added dropwise and thereaction mixture was stirred for 1.5 h. The mixture was warmed to 0° C.and stirred for 1 h. The mixture was then diluted with saturated aqueoussolution of NaHCO₃ (50 mL) and the separated aqueous layer was extractedwith DCM (2×30 mL). The combined organic layers were washed with brine,then dried (Na₂SO₄), filtered and concentrated under reduced pressure.The material was purified by column chromatography on silica gel (40 g)using a gradient of 0-30% EtOAc in hexane as eluent to afford the bisacetate intermediate. MS (ESI) [M+Na]⁺819.5.

To a solution of above material in MeOH (10 mL), NaOMe (4.62 M in MeOH,0.56 mL, 2.59 mmol) was added and the reaction mixture was stirred atroom temperature for 2 h. The mixture was concentrated under reducedpressure and the residue was diluted in DCM and saturated NH₄Cl (100mL). The separated aqueous layer was extracted with DCM (2×30 mL). Thecombined organic layers were washed with brine, then dried (Na₂SO₄),filtered and concentrated under reduced pressure. The material waspurified by preparative HPLC (BEH 30×150 mm C18 ACN/AmForm 73-80%) toafford to afford the title compound (first eluting, 31 mg) along with P2(second eluting, 70.9 mg). MS (ESI) [M+Na]⁺735.4.

Step 8(1S,2R,3R,4S,6R)-4,6-diamino-3-[(2R,3R,6S)-3-amino-6-[(1S)-1-amino-2-hydroxy-ethyl]tetrahydropyran-2-yl]oxy-cyclohexane-1,2-diol,acetic acid

To a solution of benzylN-[(1S)-1-[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]-2-benzyloxy-ethyl]-N-benzyl-carbamate(25 mg, 0.035 mmol) in tetrahydrofuran (1 mL), was added trimethylphosphine (0.21 mL 1.0 M tetrahydrofuran solution, 0.21 mmol) at roomtemperature and the reaction mixture was heated to 65° C. for 30 min.The mixture was diluted 0.1 M aq. sodium hydroxide (0.42 mL, 0.042 mmol)and the mixture was stirred for 5 h. The mixture was cooled to roomtemperature and stirred overnight. The volatiles were concentrated underreduced pressure and the material was purified with reverse phasechromatography on C18 using 10-100% AcCN in H₂O (ammonium formate:Formicacid 1:1. 0.1%) to amine. MS (ESI) [M+Na]⁺657.5.

To a solution of above material in a mixture of water:MeOH:AcOH(1:0.5:0.1, 5 mL), was added palladium(II) hydroxide (20 wt % loading oncarbon, 24.6 mg, 0.018 mmol). The suspension was hydrogenated underhydrogen atmosphere for 16 h. The mixture was filtered and the filtratedwas concentrated under reduced pressure and then lyophilized to affordthe title compound (18.4 mg, 90%) as a salt. ¹H NMR (500 MHz, MeOD) δ5.85 (d, J=3.0 Hz, 1H), 4.20-4.11 (m, 1H), 3.78 (dd, J=11.9, 4.2 Hz,1H), 3.75-3.64 (m, 2H), 3.52 (t, J=9.1 Hz, 1H), 3.39 (t, J=9.3 Hz, 1H),3.37-3.33 (m, 1H), 3.15 (dt, J=9.5, 8.6 Hz, 2H), 3.06 (t, J=9.2 Hz, 1H),2.30 (d, J=12.5 Hz, 1H), 2.09-2.02 (m, 1H), 1.72 (dd, J=25.0, 12.7 Hz,1H), 1.62-1.48 (m, 1H). 2H missing (in the 1.9 ppm peak together withacetic acid according to HSQC). MS (ESI) [M+H]⁺321.2.

Example 41

(1S,2R,3R,4S,6R)-4,6-diamino-3-[(2R,3R,6S)-3-amino-6-[(1S)-1-amino-2-fluoroethyl]tetrahydropyran-2-yl]oxy-cyclohexane-1,2-diol,formic acid

To a mixture of benzylN-[(1S)-1-[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]-2-fluoro-ethyl]-N-benzyl-carbamate(see Example 23 for synthesis, 10 mg, 0.016 mmol) and 10% Pd/C (5.1 mg,0.0048 mmol) was added anhydrous MeOH (1 mL). Nitrogen was bubbled for 5min, then ammonium formate (9.1 mg, 0.14 mmol) was added and the mixturewas heated at 63° C. for 6 h. The mixture was cooled to room temperatureand then filtered through a nylon filter (45 μm) and the volatiles wereevaporated under reduced pressure then lyophilized (1 drop of formicacid in water) to provide the title compound (2.7 mg, 33%) as formatesalt. ¹H NMR (500 MHz, MeOD) δ 8.21 (s, 4H), 5.85 (d, J=3.5 Hz, 1H),4.82-4.68 (m, 2H), 4.38 (d, J=12.3 Hz, 1H), 3.93 (t, J=9.6 Hz, 1H),3.74-3.67 (m, 1H), 3.60 (t, J=9.2 Hz, 1H), 3.46-3.39 (m, 3H), 3.20 (ddd,J=11.0, 10.0, 3.5 Hz, 1H), 2.39 (dt, J=12.4, 4.1 Hz, 1H), 2.22-2.12 (m,1H), 2.06-1.96 (m, 1H), 1.94-1.83 (m, 2H), 1.74-1.64 (m, 1H). MS (ESI)[M+H]⁺323.2.

Example 42

Step 1 BenzylN-benzyl-N-[[(2S,5R,6R)-5-(benzyloxycarbonylamino)-6-[[(1R,5S,6R,7R,8S)-7,8-dihydroxy-3-oxo-2,4-diazabicyclo[3.3.1]nonan-6-yl]oxy]tetrahydropyran-2-yl]methyl]carbamate

PMe₃ (1.0 M in THF, 1.14 mL, 1.14 mmol) was added to a solution ofbenzylN-[[(2S,5R,6R)-5-azido-6-[(1R,2R,3S,4R,6S)-4,6-diazido-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]methyl]-N-benzyl-carbamate(see Example 11 for synthesis, 150 mg, 253 μmol) and water (150 μL, 8.33mmol) in THF (6.0 mL) under N₂ at ambient temperature. The reaction waswarmed to 40° C. under a refluxing condenser. After 18 h, the solutionwas cooled to room temperature and K₂CO₃ (315 mg, 2.28 mmol) was addedfollowed by water (1.5 mL). After another 30 min, CbzCl (162 μL, 1.14mmol) was added dropwise and the reaction mixture was stirred at for 2h. The volatiles were evaporated under reduced pressure and the materialwas purified by silica gel chromatography (12 g cartridge) with using agradient of EtOAc and hexane (30-80%) as eluent then 30% MeOH in DCM toproduce benzylN-benzyl-N-[[(2S,5R,6R)-5-(benzyloxycarbonylamino)-6-[(1R,2R,3S,4R,6S)-4,6-bis(benzyloxycarbonylamino)-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]methyl]carbamate(282 mg).

LiOHH₂O (70 mg, 1.68 mmol) was added to a suspension of benzylN-benzyl-N-[[(2S,5R,6R)-5-(benzyloxycarbonylamino)-6-[(1R,2R,3S,4R,6S)-4,6-bis(benzyloxycarbonylamino)-2,3-dihydroxy-cyclohexoxy]tetrahydropyran-2-yl]methyl]carbamate(220 mg, 240 μmol) in a mixture dioxane and H₂O (2.25 mL 2:1) in amicrowave tube. The tube was sealed and the reaction mixture was warmedto 50° C. for 18 h. The mixture was filtered through silica gel (4.0 g)and eluted with a mixture of MeOH in DCM (80.0 mL, 4:1). To the filtratewas added HOAc (150 μL) and the mixture was concentrated under reducedpressure. The material was purified by preparative HPLC (BEH 30×150 mmC18 ACN/AmForm 40-60%) to provide the title compound (20 mg, 12% over 3steps) as a solid. MS (ESI) [M+H]⁺675.3.

Step 2(1R,5S,6R,7R,8S)-6-[(2R,3R,6S)-3-amino-6-(aminomethyl)tetrahydropyran-2-yl]oxy-7,8-dihydroxy-2,4-diazabicyclo[3.3.1]nonan-3-one;formic acid

Pd(OH)₂/C (10 wt %, 25 mg, 18 μmol) was added to a solution of benzylN-benzyl-N-[[(2S,5R,6R)-5-(benzyloxycarbonylamino)-6-[[(1R,5S,6R,7R,8S)-7,8-dihydroxy-3-oxo-2,4-diazabicyclo[3.3.1]nonan-6-yl]oxy]tetrahydropyran-2-yl]methyl]carbamate(20 mg, 30 μmol) in MeOH (1.0 mL) under N₂ at ambient temperature. H₂was bubbled through the suspension for 15 min and the mixture wasstirred under hydrogen atmosphere for 18 h. The mixture was filteredthrough a frit (0.45 μm diameter) and the filtrate was concentratedunder reduced pressure. The material was purified by preparative HPLC(BEH 30×150 mm ACN/AmForm 10% ISO) to provide the title compound(bis-formate, 9.0 mg, 74%). ¹1-INMR (500 MHz, MeOD) δ 8.57 (s, 2H), 5.21(s, 1H), 4.05 (t, J=9.8 Hz, 1H), 3.98-3.86 (m, 3H), 3.68 (s, 1H), 3.50(s, 1H), 3.37 (s, 1H), 3.13 (d, J=12.7 Hz, 1H), 2.99 2.88 (m, 1H), 2.60(d, J=13.1 Hz, 1H), 1.98 1.89 (m, 2H), 1.85 (d, J=12.5 Hz, 1H), 1.66 (d,J=13.1 Hz, 1H), 1.59 1.47 (m, 1H). MS ESI [M+H]⁺317.2.

Example 43

(2S,3R,4S,5R)-2-(((1R,2R,3S,5R,6S)-3,5-diamino-2-(((2R,3R,5S,6R)-3-amino-6-(aminomethyl)-5-hydroxytetrahydro-2H-pyran-2-yl)oxy)-6-hydroxycyclohexyl)oxy)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol

BtrL is prepared as a cell free extract (CFE), flash frozen in liquidnitrogen, and stored in 50 mM HEPES buffer (pH 8.0) at −80° C. NeoP ispurified, flash frozen in liquid nitrogen, and stored in 20 mM Trisbuffer (pH 7.5), supplemented with 200 mM KCl at −80° C.5-phospho-D-ribose 1-diphosphate pentasodium salt (PRPP) is purchasedfrom Sigma-Aldrich®. Ribosylation reaction conditions are as follows:50% v/v BtrL CFE, nebramine (30.6 mg, 0.10 mmol, 10 mM finalconcentration), 10 mM PRPP (final concentration), 1 mM MgCl₂, 50 mMHEPES buffer (pH 7.5) (final concentration), 10% glycerol (final) and10% v/v purified NeoP. The reaction is incubated at 30° C. with rotationfor 16 hours (not exceeding 24 hours) to allow for successfulinstallation of the ribose to the nebramine substrate. The reaction isthen heat inactivated at 98° C. for 2 minutes to allow proteinprecipitation to occur. To remove the precipitated protein, the reactionis then spun at 12,000 rpm for 30 minutes. The supernatant is thenpurified by ion exchange with Amberlyst CG50 resin to separate andconcentrate the target aminoglycoside molecule from contaminatingneutral and cationic molecules. The aminoglycoside molecule is elutedwith 3% NH₄OH₄ and fractions containing the desired product arelyophilized. The lyophilized aminoglycoside is then further purified bypreparative HPLC. The product was dissolved in water, two equivalents ofsulfuric acid was added and the solution was lyophilized to give thesulfate salt (5.1 mg, 0.0080 mmol, 8.0%). LCMS m/z ES+[M+H]+: 439.2

Example 44

(2S,3R,4S,5R)-2-(((1R,2R,3S,5R,6S)-3,5-diamino-2-(((2R,3S,4S,5R,6R)-3-amino-6-(aminomethyl)-4-fluoro-5-hydroxytetrahydro-2H-pyran-2-yl)oxy)-6-hydroxycyclohexyl)oxy)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol

310 μL of buffer mix (250 mM HEPES, 5 mM MgCl₂, 50% glycerol) wascombined with 775 μL of cell-free extract from BL-21 e. coli expressingBtrL and 155 μL of 100 mM PRPP (in H₂O) and 155 μL of NeoP (5 mg/mL) ina 2 mL Eppendorf tube. Next, 155 μL of(1S,2R,3R,4S,6R)-4,6-diamino-3-4(2R,3S,4S,5R,6R)-3-amino-6-(aminomethyl)-4-fluoro-5-hydroxytetrahydro-2H-pyran-2-yl)oxy)cyclohexane-1,2-diol(100 mM in H₂O) was added and the reaction incubated at 30° C. for 16hours. The reaction was then heated at 95° C. for 10 minutes andcentrifuged at 12,000 rpm to removed solids. The supernatant was appliedto 1 g of Amberlyst CG50 ion exchange resin (pre-equilibrated with 20 mLH₂O). The loaded resin was washed with 12 mL of H₂O and theaminoglycoside was eluted with 3×1 mL portions of 3% NH₄OH. The combinedelutions were lyophilized to yield a white solid that contained productand remaining starting material. The solids were taken up inconcentrated NH₄OH, loaded onto a C18 column, and eluted with a gradientof 0-30% acetonitrile in 0.1 M NH₄OH to yield 0.4 mg of(2S,3R,4S,5R)-2-(((1R,2R,3S,5R,6S)-3,5-diamino-2-(((2R,3S,4S,5R,6R)-3-amino-6-(aminomethyl)-4-fluoro-5-hydroxytetrahydro-2H-pyran-2-yl)oxy)-6-hydroxycyclohexyl)oxy)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol.LCMS: expected [M+1H]⁺=457.2, found 457.2.

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon-patent publications referred to in this specification areincorporated herein by reference, in their entirety to the extent notinconsistent with the present description.

From the foregoing it will be appreciated that, although specificembodiments of the disclosure have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the disclosure. Accordingly, the disclosure isnot limited except as by the appended claims.

1-54. (canceled)
 55. A process for preparing a compound of formula A-5,

or a salt thereof, wherein: R^(1a) and R^(1b) are independently selectedfrom the group consisting of H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl,and heteroaryl, wherein the alkyl, cycloalkyl, aryl, or heteroaryl isunsubstituted or substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, alkyl, aryl,heteroaryl, —SR¹², —SO₂R¹³, —OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, andwherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; orR^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴, R²⁵, and —OR²⁶, and wherein each R²², R²³, R²⁴, R²⁵, andR²⁶ is independently H or alkyl, wherein the alkyl is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶; R^(2a),R^(2b), R^(3a) and R^(3b) are independently selected from the groupconsisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, and C₁-C₆alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H, alkyl, aminoprotecting group, or hydroxyl protecting group; wherein the C₁-C₆ alkylor alkyl is unsubstituted or substituted with one or more substituentsselected from the group consisting of aryl, halogen, —OR³⁰, —NR³¹R³²,—SR³³, and —SO₂R³⁴; wherein each R³⁰, R³¹, R³², R³³, and R³⁴ isindependently H or alkyl substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,NR¹⁴R¹⁵, and —OR¹⁶; or R^(2a) and R^(2b) form an oxo or imino groupsubstituted with C₁-C₆ alkyl; R^(3a) and R^(3b) form an oxo or iminogroup substituted with C₁-C₆ alkyl; X¹ is —F, —Cl, —Br, or —I; LVG¹ is aleaving group; N^(1a) is —NHPg^(1a), —N(Pg^(1a))₂, or N₃, wherein eachPg^(1a) is independently an amino protecting group; m is zero, 1, or 2;n is zero, 1, or 2; and, wherein m+n is 1, 2 or 3; the processcomprising: (a) contacting a compound of formula A-1:

or a salt thereof, with a chiral auxiliary reagent to yield a compoundof formula A-2:

or a salt thereof, wherein Xc is a chiral auxiliary group; (b)contacting the compound of formula A-2 with a Grignard or organolithiumreagent to yield a compound of formula A-3:

or a salt thereof; (c) contacting the compound of formula A-3 with ahalogen reagent in presence of a nucleophile reagent (Nuc-1) to yield acompound of formula A-4:

or a salt thereof; wherein: X¹ is —F, —Cl, —Br, or —I; Nuc-1 is LVG¹-M,wherein M is H, a metal cation, a non-metal cation, or a lone pair ofelectrons; LVG¹ is a leaving group; and (d) exchanging the chiralauxiliary group for an amino protecting group in the compound of formulaA-4 by reaction with an amino protecting group reagent to yield thecompound of formula A-5.
 56. The process of claim 55, further comprisingafter step (d): (e) converting X¹ in the compound of formula A-5 to X toyield a compound of formula A-6:

or a salt thereof, wherein X is —NH₂, —N₃, a protected amino group, —OH,or a protected hydroxyl group.
 57. A process for preparing a compound offormula A-5a,

or a salt thereof, wherein: R^(1a) and R^(1b) are independently selectedfrom the group consisting of H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl,and heteroaryl, wherein the alkyl, cycloalkyl, aryl, or heteroaryl isunsubstituted or substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, alkyl, aryl,heteroaryl, —SR¹², —SO₂R¹³, —OSF₂NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, andwherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; orR^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴R²⁵, and —OR²⁶, and wherein each R²², R²³, R²⁴, R²⁵, andR²⁶ is independently H or alkyl, wherein the alkyl is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, —NR¹⁴R¹⁵, and —OR¹⁶; R^(2a), andR^(3a) are independently selected from the group consisting of H, —OR²⁷,—NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, and C₁-C₆ alkyl, wherein each R²⁷,R²⁸, and R²⁹ is independently H or alkyl; wherein the C₁-C₆ alkyl oralkyl is unsubstituted or substituted with one or more substituentsselected from the group consisting of aryl, halogen, —OR³⁰, —NR³¹R³²,—SR³³, and —SO₂R³⁴; wherein each R³⁰, R³¹, R³², R³³, and R³⁴ isindependently H or alkyl substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,NR¹⁴R¹⁵, and —OR¹⁶; or R^(2a) and R^(2b) form an oxo or imino groupsubstituted with C₁-C₆ alkyl; R^(3b) is H; N^(1b) is —NHPg^(1b),—N(Pg^(1b))₂, or N₃, wherein Pg^(1b) is an amino protecting group; X² is—F, —Cl, —Br, or —I; LVG² is a leaving group. m is zero, 1, or 2; n iszero, 1, or 2; wherein m+n is 1, 2 or 3; the process comprising: (a)converting —OH in a compound of formula A-7

or a salt thereof, to R^(1a) to yield a compound of formula A-8:

or a salt thereof; and (b) contacting the compound of formula A-8 with ahalogen reagent in the presence of a nucleophile reagent (Nuc-2) toyield the compound of formula A-5a, wherein Nuc-2 is LVG²-M, wherein Mis H, a metal cation, a non-metal cation, or a lone pair of electrons.58. The process of claim 57, further comprising after step (b): (c)converting X² in the compound of formula A-5a to X to yield a compoundof formula A-6a:

or a salt thereof, wherein X is —NH₂, —N₃, a protected amino group, —OH,or a protected hydroxyl group.
 59. A process for preparing a compound offormula B-6′:

or a salt thereof, wherein: R^(4aa) and R^(4bb) are, independently H,—OH, —OR⁴⁰, —NR⁴¹R⁴², or halogen; wherein each R⁴⁰, R⁴¹, and R⁴² areindependently H, alkyl, —CONH₂, or —COCH₃; wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl, substitutedaryl, heteroaryl, halogen, and substituted heteroaryl; R^(5aa) is H,—CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl is unsubstituted orsubstituted with one or more substituents selected from the groupconsisting of —OH, —OC(O)CH₃, —NH₂, —CN, CONH₂, and halogen; R^(6a) andR^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy, —OC(O)CH₃,or —OPg^(2o), wherein Pg^(2o) is a hydroxyl protecting group; R⁸ is H,C₁-C₆ alkyl, an amino protecting group, or

wherein: Q¹ is NH, O, or S; z is an integer from 0 to 4, R^(35z) is H orC₁-C₃ alkyl; each R^(36z) and R^(37z) is independently selected from thegroup consisting of H, alkyl, halogen, and —OH, and R^(38z) is H, alkyl,or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) and R^(40z) are independentlyH or C₁-C₃ alkyl; or R^(35z) and R^(38z), together with the atoms towhich they are attached, form a heterocycloalkyl group comprising atleast one N; R^(8b) is H or C₁-C₃alkyl; N^(1c) is —NHPg^(1c) or N₃,wherein Pg^(1c) is an amino protecting group Pg^(2b) is a hydroxylprotecting group; o is zero, 1, or 2; p is zero, 1, or 2; wherein o+p is1, 2 or 3; the process comprising: (a) contacting a compound of formulaB-1′:

or a salt thereof, with an amino protecting group reagent and a hydroxylprotecting group reagent to yield a compound of formula B-2′:

or a salt thereof; wherein Pg^(2a) is a hydroxyl protecting group; (b)converting the amino group of the compound of formula B-2′ at C1 to anazide group; (c) converting the azide group of the compound of formulaB-2′ at C1 to a hydroxyl group; (d) oxidizing the hydroxyl group of thecompound of formula B-2′ at C1 to an oxo group to yield a compound offormula B-3′:

or a salt thereof; (e) converting the oxo group of the compound offormula B-3′ to an imino group and contacting with an amino reactivereagent to yield a compound of formula B-4′:

or a salt thereof; contacting the compound of formula B-4′ with aGrignard or organolithium reagent to yield a compound of formula B-5′:

or a salt thereof; and (g) forming a hydroxyl group by selective removalof the Pg^(2a) protecting group of the compound of formula B-5′ to yieldthe compound of formula B-6′.
 60. The process of claim 59, wherein thestereochemistry in the ring of formulae B-1′, B-2′, B-3′, B-4′, B-5′,and B-6′ is as indicated in formula B″, wherein

indicates a point of attachment to a hydrogen or a moiety:


61. A process for preparing a compound of formula B-11′

or a salt thereof, wherein: R^(4aa) and R^(4bb) are independently H,—OH, —OR⁴⁰, —NR⁴¹R⁴², or halogen; wherein each R⁴⁰, R⁴¹, and R⁴² areindependently H, alkyl, —CONH₂, or —COCH₃; wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl, substitutedaryl, heteroaryl, halogen, and substituted heteroaryl; R^(6a) and R^(6b)are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy, —OC(O)CH₃, or—OPg^(2o); wherein Pg^(2o) is a hydroxyl protecting group; N^(1s) is N₃or —NR⁸R^(8b); R⁸ is H, C₁-C₆ alkyl, an amino protecting group, or

wherein: Q¹ is NH, O, or S; z is an integer from 0 to 4, R^(35z) is H orC₁-C₃ alkyl; each R^(36z) and R^(37z) is independently selected from thegroup consisting of H, alkyl, halogen, and —OH, and R^(38z) is H, alkyl,or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) and R^(40z) are independentlyH or C₁-C₃ alkyl; or R^(35z) and R^(38z), together with the atoms towhich they are attached, form a heterocycloalkyl group comprising atleast one N; R^(8b) is H or C₁-C₃alkyl; N^(1d) is —NHPg^(1d) or N₃,wherein Pg^(1d) is an amino protecting group; Pg^(2d) is a hydroxylprotecting group; o is zero, 1, or 2; p is zero, 1, or 2; wherein o+p is1, 2 or 3; the process comprising: (a) contacting a compound of formulaB-8′:

or a salt thereof, wherein N^(1dx) is —NH₂, —NHPg^(1d) or N₃ whereinPg^(1d) is an amino protecting group, with a first selective hydroxylprotecting group reagent; a second selective hydroxyl protecting groupreagent; an amino protecting group reagent, if N^(1dx) is —NH₂; and anamino reactive reagent, if N^(1s) is —NR⁸R^(8b), to yield a compound offormula B-9′:

or a salt thereof; wherein Pg^(2c) is a hydroxyl protecting group; (b)contacting the compound of formula B-9′ with an electrophilic reagent;or oxidizing the OH at C6 to an oxo group and contacting the oxo groupwith a nucleophilic reagent to yield a compound of formula B-10′:

or a salt thereof; and c) forming a hydroxyl group by selective removalof the Pg^(2c) protecting group of the compound of formula B-10′ toyield the compound of formula B-11′.
 62. The process of claim 61,wherein the stereochemistry in the ring of formulae B-8′, B-9′, andB-11′ is as indicated in formula B″, wherein

indicates a point of attachment to a hydrogen or a moiety:


63. A process for preparing a compound of formula AB-1′,

or a salt thereof, wherein: R^(1a) and R^(1b) are independently selectedfrom the group consisting of H, C₁-C₁₂ alkyl, C₁-C₆ cycloalkyl, aryl,and heteroaryl, wherein the alkyl, cycloalkyl, aryl, or heteroaryl isunsubstituted or substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, alkyl, aryl,heteroaryl, —SR¹², —SO₂R¹³, —OSF²NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —N₃, and —OR¹⁶, andwherein each R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is independently H or alkyl; orR^(1a) and R^(1b), together with the atom to which they are attached,form a cycloalkyl group or a heterocycloalkyl group, wherein thecycloalkyl group or heterocycloalkyl group is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR²²,—SO₂R²³, —NR²⁴, R²⁵, and —OR²⁶, and wherein each R²², R²³, R²⁴, R²⁵ andR²⁶ is independently H or alkyl, wherein the alkyl is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, NR¹⁴R¹⁵, and —OR¹⁶, R^(2a),R^(2b), R^(3a) and R^(3b) are independently selected from the groupconsisting of H, —OR²⁷, —NR²⁸R²⁹, halogen, C₁-C₄ cycloalkyl, and C₁-C₆alkyl, wherein each R²⁷, R²⁸, and R²⁹ is independently H, alkyl, aminoprotecting group, or hydroxyl protecting group; wherein the C₁-C₆ alkylor alkyl is unsubstituted or substituted with one or more substituentsselected from the group consisting of aryl, halogen, —OR³⁰, —NR³¹R³²,—SR³³, and —SO₂R³⁴; wherein each R³⁰, R³¹, R³², R³³, and R³⁴ isindependently H or alkyl substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,NR¹⁴R¹⁵, and —OR¹⁶; or R^(2a) and R^(2b) form an oxo or imino groupsubstituted with C₁-C₆ alkyl; R^(3a) and R^(3b) form an oxo or iminogroup substituted with C₁-C₆ alkyl; R^(4aa) and R^(4bb) are,independently H, —OH, —OR⁴⁰, —NR⁴¹R⁴², or halogen; wherein each R⁴⁰,R⁴¹, and R⁴² are independently H, alkyl, —CONH₂, or —COCH3; wherein thealkyl is unsubstituted or substituted with one or more substituentsselected from the group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl,substituted aryl, heteroaryl, halogen, and substituted heteroaryl;R^(5aa) is H, —CN, —CONH₂ or C₁-C₃alkyl, wherein the alkyl isunsubstituted or substituted with one or more substituents selected fromthe group consisting of —OH, —OC(O)CH₃, —NH₂, —CN, —CONH₂, and halogen;R^(6a) and R^(6b) are, independently H, halogen, NH₂, —OH, C₁-C₃alkoxy,—OC(O)CH₃, or —OPg^(2m); wherein Pg^(2m) is a hydroxyl protecting group;N^(1s) is N₃ or —NR^(8a)R^(8b); R^(8a) is H, C₁-C₆ alkyl, an aminoprotecting group, or

wherein Q¹ is NH, O, or S; z is an integer from 0 to 4, R^(35z) is H orC₁-C₃ alkyl; each R^(36z) and R^(37z) is independently selected from thegroup consisting of H, alkyl, halogen, and —OH, and R^(38z) is H, alkyl,or —C(═NH)NR^(39z)R^(40z), wherein R^(39z) and R^(40z) are independentlyH or C₁-C₃ alkyl; or R^(35z) and R^(38z), together with the atoms towhich they are attached, form a heterocycloalkyl group comprising atleast one N; R^(8b) is H or C₁-C₃alkyl; N^(1e) is —OH, protectedhydroxyl group, —NHPg^(1e) or N₃, wherein Pg^(1e) is an amino protectinggroup; N^(1f) is —NHPg^(1f) or N₃, wherein Pg^(1f) is an aminoprotecting group; Pg^(2e) is a hydroxyl protecting group; X⁷ is H, —NH₂,—N₃, protected amino group, —OH, protected hydroxyl group, or halogen; mis zero, 1, or 2; n is zero, 1, or 2; wherein m+n is 1, 2 or 3; o iszero, 1, or 2; p is zero, 1, or 2; wherein o +p is 1, 2 or 3; theprocess comprising: (a) contacting a compound of formula A-9′:

wherein LVG³ is a leaving group, with a compound of formula B-12:

to yield the compound of formula AB-1′.
 64. The process of claim 63,further comprising after step (a): (b) if amino protecting groups andhydroxyl protecting groups are present, removing the amino protectinggroups and hydroxyl protecting groups to yield a compound of formulaAB-2′, or a salt thereof,


65. The process of claim 63, further comprising after step (a): (b)selectively deprotecting the compound of formula AB-1′ by removing thePg^(2e) moiety to yield a compound of formula AB-3′:

or a salt thereof; (c) contacting the compound of formula AB-3′ with acompound of formula C-1,

or a salt thereof, wherein: R^(7a), R^(7b), and R^(7c) are independentlyH, NH₂, OH, —OR⁷¹ or —OPg^(2r); wherein R⁷¹ is alkyl; wherein the alkylis unsubstituted or substituted with one or more substituents selectedfrom the group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl,substituted aryl, heteroaryl, halogen, and substituted heteroaryl;wherein Pg^(2r) is a hydroxyl protecting group; R^(9a) and R^(9b) areindependently H, OH, or —OR⁹¹, wherein R⁹¹ is alkyl, alkenyl, oralkynyl; wherein the alkyl, alkenyl, and alkynyl is unsubstituted orsubstituted with one or more substituents selected from the groupconsisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl,heteroaryl, and substituted heteroaryl; R^(10a) and R^(10b) areindependently H, OH, or —OR¹⁰¹, wherein R¹⁰¹ is alkyl, alkenyl, oralkynyl; wherein the alkyl, alkenyl, or alkynyl is unsubstituted orsubstituted with one or more substituents selected from the groupconsisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl,heteroaryl, and substituted heteroaryl; Pg^(2f) is a hydroxyl protectinggroup; LVG⁴ is a leaving group; q is zero, 1, or 2; r is zero, 1, or 2;wherein q+r is 1, 2 or 3; to yield a compound of formula ABC-1′:

or a salt thereof.
 66. The process of claim 65, wherein thestereochemistry in the ring of formula ABC-1′ is as indicated in formulaABC″,


67. The process of claim 65, further comprising after step (c): (d) ifamino protecting groups and hydroxyl protecting groups are present,removing the amino protecting groups and hydroxyl protecting groups toyield a compound of formula ABC-2′:

or a salt thereof.
 68. The process of claim 65, wherein thestereochemistry in the ring of formula ABC-2′, is as indicated informula ABC″,


69. The process of claim 63, further comprising after step (a): (b)selectively deprotecting the compound of formula AB-1′ by removing thePg^(2e) moiety to yield a compound of formula AB-3′:

or a salt thereof; (c) contacting the compound of formula AB-3′ with acompound of formula CD-1,

or a salt thereof, wherein: R^(7a), R^(7b), and R^(7c) are independentlyH, NH₂, OH, —OR⁷¹ or —OPg^(2r); wherein R⁷¹ is alkyl; wherein the alkylis unsubstituted or substituted with one or more substituents selectedfrom the group consisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl,substituted aryl, heteroaryl, halogen, and substituted heteroaryl;wherein Pg^(2r) is a hydroxyl protecting group; R^(9a) and R^(9b) areindependently H, OH, or —OR⁹¹, wherein R⁹¹ is alkyl, alkenyl, oralkynyl; wherein the alkyl, alkenyl, and alkynyl is unsubstituted orsubstituted with one or more substituents selected from the groupconsisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl,heteroaryl, and substituted heteroaryl; R^(10a) and R^(10b) areindependently H, OH, or —OR¹⁰¹, wherein R¹⁰¹ is alkyl, alkenyl, oralkynyl; wherein the alkyl, alkenyl, and alkynyl is unsubstituted orsubstituted with one or more substituents selected from the groupconsisting of —CONH₂, —OH, —NH₂, —COCH₃, aryl, substituted aryl,heteroaryl, and substituted heteroaryl; LVG⁵ is a leaving group; N^(1g)is —NHPg^(1g) or N₃, wherein Pg^(1g) is an amino protecting group;N^(1h) is —NHPg^(1h) or N₃, wherein Pg^(1h) is an amino protectinggroup; Pg^(2g) is a hydroxyl protecting group; Pg^(2h) is a hydroxylprotecting group; q is zero, 1, or 2; r is zero, 1, or 2; wherein q+r is1, 2 or 3; to yield a compound of formula ABCD-1:

or a salt thereof.
 70. The process of claim 69, wherein thestereochemistry in the ABCD-1′ ring is as indicated in formula ABCD″:


71. The process of claim 69, further comprising after step (c): (d) ifamino protecting groups and hydroxyl protecting groups are present,remove the amino protecting groups and hydroxyl protecting groups toyield a compound of formula ABCD-2′, or a salt, solvate, enantiomer, ordiastereomer thereof,


72. The process of claim 71, wherein the stereochemistry in the ABCDring are indicated as in formula ABCD″:


73. A compound selected from the group consisting of: a compound offormula A-10′; a compound of formula B-13′; a compound of formula AB-4′;a compound of formula AB-5′; a compound of formula AB-1′; a compound offormula AB-2″; a compound of formula ABC-3; a compound of formulaABC-4′; a compound of formula ABC-1; a compound of formula ABC-2″; acompound of formula ABCD-3; and a compound of formula ABCD-4′.
 74. Apharmaceutical composition comprising a compound of claim 73, or apharmaceutically acceptable salt, solvate, stereoisomer, or tautomerthereof, and a pharmaceutically acceptable carrier.
 75. A method fortreating a bacterial infection in a subject, comprising administering toa subject in need thereof a therapeutically effective amount of acompound of claim 73, or a pharmaceutically acceptable salt, solvate,stereoisomer, or tautomer thereof.